1996 practice parameters for allergen immunotherapy. jaci

8/13/2019 1996 Practice Parameters for Allergen Immunotherapy. JACI

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T H E J O U R N A L O FL L E R G Y

A N DC L I N I C L I M M U N O L O G Y

V O L U M E 9 8 N U M B E R 6 P A R T 1

r a c t i c e p a r a m e t e r sr ac t ice par amete r s fo ra l l e r g e n i m m u n o t h e r a p y

T h e s e p a r a m e t e r s w e r e d e v e l o p e d b y th e J o i n t T a s kF o r c e o n P r a ct i ce P a r a m e t e r s r e p r e s e n t i n g t h eA m e r ic a n A c a d e m y o f A l le r g y A s t h m a a n d Im m u n o l o g y t h eA m e r i ca n C o l l eg e o f A l l e r g y A s t h m a a n d I m m u n o l o g y a n dt h e J o i n t C o un c il o f A l l e rg y A s t h m a a n d I m m u n o l o g y .E d i t o rs : R i c h a rd A . N i c k l a s M D I . L e o n a r d B e r n s t e in M DJ o a n n B l e s s in g - M o o r e M D S t a n l e y M . F i n e m a n M DA r n o l d A . G u t m a n M D R u f u s E . L e e M D J a m e s T . L i M D P h DW i ll i a m E . B e r g e r M D a n d S h e l d o n L. S p e c t o r M DC o n t r i b u t o r s : I. L e o n a r d B e r n s t e i n M D R i c h a r d N i c k l a s M D a n d o t h e rm e m b e r s o f t h e J o i n t T a s k F o rc e P a u l G r e e n b e r g e r M DD a v i d P e a r lm a n M D S t a n l e y Z e i tz M D a n d M i c h a e l B l ais s M DR e v i e w e rs : J o h n J . C o n d e m i M D M a r k S . D y k e w i c z M DS t a n l e y M . F i n e m a n M D P a u l J . H a n n a w a y M D R i c ha r d F . L o c k ey M DS c o t t S . N i c h o la s M D M i c h a e l J . R e i d M D G a l l G . S h a p i r o M D a n dR o b e rt A . W o o d M D

T h e A m e r i c a n A c a d e m y o f A l l e r g y , A s th m a a n d I m m u n o lo g y( A A A A I ) a n d t h e A m e r i c a n C o l l e g e o f A l le r g y , A s th m a a n dI m m u n o lo g y ( A C A A I ) h a v e j o in t l y a c c e p t e d r e s p o n s ib i l i t yfor es tab l ish ing a l le rgen immunotherapy parameters . Be-cause th is document incorpora ted the e f for ts o f many par t ic -ipan ts , no s ing le ind iv idua l , inc lud ing those who served onthe Jo in t Task Force , i s au thor ized to p rov ide an of f ic ia lA A A A I o r A C A A I i n t e r p r e t a t i o n o f t h e s e P r a e l i c e P a r a m -e t e rs . A n y r e q u e s t f o r i n f o r m a t io n a b o u t o r a n i n t e r p r e t a t i o no f t h e s e P r a c t i c e P a r a m e te r s b y t h e A A A A I o r t h e A C A A Is h o u ld b e d i r e c t e d t o t h e E x e c u t i v e O f fi ce s o f t h e A A A A I ,t h e A C A A I , a n d t h e J o in t C o u n c i l o f A l l e r g y , A s th m a a n dI m m u n o lo g y .

I mmu n i t y h a s b e e n d e f i n e d a s a f r e e d o m f r o m o rprotect ion against certain diseases . The ini t ial immu-no therap eu t i c in t e rven t ions which inc luded the de-ve lopment o f p reven t ive vacc ines and xenogeneic

Rec eived for publ ica t ion Aug. 29 , 1996; accep ted fo r publ ica-tion Aug. 29, 1996.Rep r in t requ es ts : AA AA I Execu t ive Off ice , 611 Eas t Wel ls S t .,Milwau kee , W1 53202 .J A l le rg y Cl in Imm unol 1996;98:1-11 .Copyr igh t 9 1996 by M osby -Ye ar Book, Inc .0091-6749/96 $5.00 + 0 1/1/77588

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1 2 Pra cti ce pa ra me te rs J ALLERGY CLLN LMMUNOLDECEMBER 1996

an t i se ra by Jenner , P as t eu r , K och , and von Behr ing ,were effect ive for disease prevent ion, These ini t iale f fo r t s a t immune modula t ion served as the modelfo r l a t e r deve lopment s in a l l e rgen immunotherapy .

O ne of the init ial invest igations of imm unizat ionfor al lergic diseases was described by Noon in 1911.H e ad min i s t e red g rass po l l en ex t rac t to pa t i en t s wi thal lergy, wi th resul t ing red uct ion s in the i r sym ptoms. 1Re c e n t a d v a n c e s i n a l l e r g e n i mmu n o t h e r a p y h a v ed e p e n d e d o n t h e i mp r o v e d u n d e r s t a n d in g o f I gE -media ted immunolog ic mechan i sms , the charac te r -izat ion of specific antigens , and the s tandardiza t ionof allergenic extracts.A l l e rg e n i m m u n o t h e r a p y i s t h e r e p e a t e d a d m i n -i s t ra t ion o f spec i f i c a l l e rgens to pa t i en t s wi th IgE-me d i a t e d c o n d i t i o n s f o r t h e p u r p o s e o f p ro v i d i n gp r o t e c t i o n a g a i n s t t h e a l l e r g i c s y mp t o ms a n d i n -f l a mm a t o r y r e a c t i o n s a s s o c i a t e d w i th n a t u r a l e x p o -su re to these a l l e rgens . The de ta i l s o f a l l e rgeni mmu n o t h e r a p y a r e e x p l a i n e d i n t h i s d o c u me n t .

T h e t e c h n iq u e o f a ll e rg e n i m m u n o t h e r a p ys h o u l d b e d i f f e r e n t i a t e d f r o m u n p r o v e n t e c h n i q u e ss u c h a s s u b l i n g u a l t r e a t me n t a n d n e u t r a l i z a t i o n -p r o v o c a t i o n t h e r a p y . A l l e r g e n i m m u n o t h e r a p ys h o u l d a l s o b e d i f f e r e n t i a t e d f r o m t h e p r o c e s s o fdesens i t i za t ion , wh ich usua l ly app l i es to the rap idprogress iv e admin i s t ra t ion o f an a l l e rgen ic sub-s t ance to render e f fec to r ce l l s l es s reac t ive .S U M M R Y S T T E M E N T S9 A l l e r g e n i mm u n o t h e r a p y i s d e f i n e d a s t h e r e -p e a t e d a d mi n i s t r a ti o n o f s p ec i f ic a ll e r g e n s t o p a -t i e n t s w i t h I g E - me d i a t e d c o n d i t i o n s , f o r t h e p u r -p o s e o f p r o v id i n g p r o t e c t i o n a g a i n s t t h e a l le r g ics y mp t o ms a n d i n f l a mma t o r y r e a c t i o n s a s s o c i a t e dw i t h n a t u r a l e x p o s u r e t o t h e s e a l l e r g e n s .9 D e s p i t e t h e v a r i e d i mmu n o l o g i c c h a n g e s o c c u r -r i n g a f t e r a l l e r g e n i mmu n o t h e r a p y , t h e p r e c i s eme c h a n i s m o r me c h a n i s ms r e s p o n s i b l e f o r c l i n i c a le f f e c ti v e n e s s h a v e n o t b e e n d e t e r m i n e d . Po s t u -l a t e d i m m u n o m o d u l a t o r y m e c h a n i s m s i n cl ud e : d e -c r e a s e i n c e l l u l a r r e s p o n s i v e n e s s , p r o d u c t i o n o fb l o c k i n g a n t ib o d y , i n d u c t i o n o f t o l e r a n c e ( B -c e l l , T - c e l l , o r b o t h ) , p r e s e n c e o f a n t i - i d i o t y p i ca n t i b o d i e s , a n d a c t i v a t io n o f T - c e l l s u p p r e s s o rm e c h a n i s m .9 Co n t r o l l e d s t u d i e s h a v e s h o w n t h a t a l l e r g e ni mm u n o t h e r a p y i s e f f e c ti v e f o r p a t i e n t s w i t h a l le r -g ic rh in i t i s o r con junc t iv i t i s , a l l e rg ic as thma, andst inging insect hypersensi t iv i ty .9 A l l e r g e n i m mu n o t h e r a p y i s i n d i c a t e d i n p a t i e n tsw h o h a v e d e mo n s t r a b l e e v i d e n c e o f s p e c i f i c I g E

an t ibod ies to c l in i ca l ly re l evan t a l l e rgens andw h o s e a l le r g ic s y m p t o ms w a r r a n t t h e t i me a n d r is ko f a l le r g e n i mm u n o t h e r a p y . T h e n e c e s s i ty f o r in i-t i a t i n g a l l e r g e n i mmu n o t h e r a p y ma y a l s o d e p e n do n t h e d e g r e e t o w h i c h s y m p t om s c a n b e r e d u c e db y me d i c a t i o n , t h e a m o u n t a n d t y p e o f me d i c a t i o nr e q u i r e d t o c o n t r o l s y m p t o m s , a n d w h e t h e r a p p r o -p r i a t e avo idance i s poss ib le .9 In choosing the com pon ents fo r a clinical ly relevantextract , the physician should know the local andregiona l aerob iology of pol lens , fungi, and dust mi tesand shou ld be aware o f po ten t i a l a l le rgens in thepa t i en t ' s env i ronment .9 The po te ncy an d s t ab i l it y o f a l l e rgen ic ex t rac t s isc ruc ia l fo r d i agnos t i c sk in t es t ing and a l l e rgeni m m u n o t h e r a p y .9 T h e m a j o r r i sk o f al l e rg e n i m m u n o t h e r a p y i sa n a p h y l a x i s . T h e r e f o r e a l l e r g e n i m m u n o t h e r a p ys h o u l d b e a d m i n i s t e r e d u n d e r t h e s u p e r v i s i o n o fa n a p p r o p r i a t e l y t r a i n e d p h y s i c i a n w h o c a n r e c -o g n i z e e a r l y s y m p t o m s a n d s i g n s o f a n a p h y l a x i sa n d a d m i n i s t e r e m e r g e n c y m e d i c a t i o n s i f n e c e s -s a r y . E v e r y e f f o r t s h o u l d b e m a d e t o p r e v e n ta n a p h y l a c t i c r e a c t i o n s c a u s e d b y al l e rg e n i m m u -n o t h e r a p y .9 A l t e r n a t i v e s t o a l le r g e n i mm u n o t h e r a p y s h o u l db e c o n s i d e r e d i n p a t ie n t s w h o s e m e d i c a l c o n d i t io nreduces the i r ab i l i t y to su rv ive a sys t emic a l l e rg icreac t ion .9 Pa t i e n t s w h o a r e r e c e i v i n g f 3 - a d r e n e r g i c - b l o c k -ing agen t s genera l ly shou ld no t rece ive a l l e rgeni m m u n o t h e r a p y .9 A l l e r g e n i m mu n o t h e r a p y o r d i n a r il y s h o u l d n o tbe in i t i a t ed dur ing p regnancy , a l though i t can andp r o b a b l y s h o u l d b e ma i n t a i n e d d u r i n g p r e g n a n c y ,p r o v i d e d t h e p a t i e n t i s t o l e r a t i n g t h e t h e r a p y w e l land has reached a dose o f ex t rac t su f f i c i en t t op r o v i d e s y mp t o ma t i c r e l i e f . T h e r e a r e n o d a t a t oi n d i c a t e t h a t i mmu n o t h e r a p y i s h a r mf u l t o t h ef e t u s . E v e r y e f f o r t s h o u l d b e ma d e t o c o n t r o l t h ep a t i e n t ' s c o n d i t i o n w i t h a p p r o p r i a t e e n v i r o n me n -t a l c o n t r o l a n d p h a r ma c o l o g i c t h e r a p y .9 T h e d u r a t io n o f a e r o al le r g e n i m m u n o t h e r a p yaf t e r max imum c l in i ca l e f f i cacy has been ach ievedi s n o t c e r t a i n . Fo r t h o s e p a t i e n t s w h o r e s p o n d ,many c l in i c i ans adv i se 4 to 5 years o f therapy .H o w e v e r , w i t h d r a w a l o f t h e r a p y a t t hi s ti me m a ye x a c e r b a t e s y mp t o ms , a n d a e r o a l l e r g e n i mmu n o -t h e r a p y ma y h a v e t o b e c o n t i n u e d f o r a mu c hl o n g e r t i me . A d e c i s i o n a b o u t w h e n t o d i s c o n t i n u e


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J ALLERGY CLIN IMMUNOL Pra cti ce pa ra me te rs 100 3VOLUME 98 NUMBER 6 PART 1

aeroallergen immunotherapy must be individual-ized.9 Several studies suggest that venom immunother-apy may be discontinued after 5 years. The deci-sion to discontinue venom immunotherapy mustbe individualized.9 Immunologic changes associated with allergenimmunotherapy include changes in levels of aller-gen-specific IgG and IgE immunoglobulins andeffects on lymphocytes, cytokines, and eosinophils.T Y P ES O F I M M U N O T H E R P Y

The majority of clinicians in the United Statesuse a weekly injection schedule that begins withone to two treatments per week, with gradualtapering of the frequency of injections when main-tenance levels are achieved. Administration ofhigh doses of allergen (e.g., 1:100 to 1:30 wt/vol orthe highest dose tolerated) is the ultimate goal forthis type of schedule. However, the weekly sched-ule often requires 6 to 12 months of increasingconcentrations before maximum or maintenancedosage is attained.Shortly after the weekly injection schedules wereintroduced by Noon, an intensive daily buildupregimen was developed. This was soon followed bya rush buildup schedule in which the allergen wasadminis tered subcutaneously every 11/2 to 2 ho urs?In the last decade, this early rush method wasmodified by a number of investigators who usedinjection schedules ranging from 10 to 30 min-utes 3, 4 The latter schedules should be more prop-erly termed r pid~rush and are similar to allergydesensitization schedules used for small molecularmass biologicals and drugs. Rapid/rush protocolsfor insect venoms and seminal plasma have beendetermined to be as efficacious and safe as injec-tion schedules for buildup to maintenance doses. 57However, an increased frequency of local andsystemic reactions is encountered duringrapid/rush desensitization to pollens and housedust mites. 8D U R T IO N O F I M M U N O T H E R P Y

It is uncertain how long aeroallergen immuno-therapy should be continued after maximum clin-ical efficacy has been achieved. For those patientswho respond, most clinicians advise at least 4 to 5years of therapy. 9' 10 (Note: If the clinical responsehas not been adequate after 2 years of treatment,aeroallergen immunotherapy should be reas-sessed.) However, exacerbation of symptoms oftenoccurs after withdrawal at these specified times,

and aeroallergen immunotherapy may have to becontinued for much longer periods. Discontinua-tion must be decided on a case-by-case basis. Inthis regard, factors that could be considered arethe degree of symptomatic improvement and thehistory of response when aeroallergen immuno-therapy was discontinued. In contrast to aeroaller-gen immunotherapy, as several studies haveshown, venom immunotherapy may be safely dis-continued after 5 years for many but not allpat ients. 11

L T E R N T IV E P P R O C H E S T O Q U E O U SI M M U N O T H E R P Y

Vehicles such as vegetable and mineral oils havebeen used to produce slow release of the allergenat the site of injection? z, 13 These are no longerrecommended because of potentially serious sideeffects. Allergens adsorbed to alum will also retardlocal allergen rel ease? 4 Adjuvant and modificationeffects for a protective immune response have beensought with the use of alum, alginates, polyethyl-ene glycol, polyvinyl alcohol, dextrorotary dipep-tides (glutamic acid-lysine), tyrosine, allergoids,and more recently, glutaraldehyde.15 Except foralum-precipitated extracts, none of these agentshas been approved for clinical use in the UnitedStates.

Local application of allergen to effector organshas been attempted for the treatment of allergicrhinitis and asthma with the rationale of inducinglocal "desensitiza tion. '16 Thus far, these treat-ments have had limited success, although a recen treport concerning the use of a lyophilized "micron-ized" allergen extract for nasal immunotherapydemonst rated objective clinical improvement. 17Some recent reports claim that oral administrationof either un-denatured or enzymatically cleavedallergens may be effective in the treatment ofallergic rhinitis. 16 However, oral or topical admin-istration of allergen in any form must still beconsidered experimental?8Subcutaneous injection of preformed antibodycomplexes has been used for the treatment ofhouse dust mite allergy.~9 Investigations of nonim-munogenic, synthetic peptides having epitopes ho-mologous to those present in natural allergenssuggest that this immunomodulatory approachmay be useful in the treatment of human aller-gy.20.

Other immunomodulatory approaches for thetreatment of allergic diseases may eventually beincluded in the general category of immunother-apy. These include the use of high-dose intrave-


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1 4 ractice parameters J A L L E R G Y C L IN I M M U N O LD E C E M B E R 9 9 6

n o u s ~ - g l o bu l in , i n t e r f e ro n - % I L - 2 , h u m a n i z e dmo n o c l o n a l a n t i b o d i e s a g a i n s t I g E , I L - 4 , I L - 1 3 ,i n t e r c e l l u l a r a d h e s i o n mo l e c u l e - I , a n d s o l u b i l i z e df r a g me n t s o f Fc e I a n d I I r e c e p t o r s .M E C H N I S M S

I mmu n o l o g i c c h a n g e s a s s o c i a t e d w i t h a l l e r g e ni mmu n o t h e r a p y i n c l u d e a n i n c r e a s e i n I g G ( b l o c k -ing) an t ibod ies , b lun t ing o f the expec ted r i se inpos t seasonal a l l e rgen-spec i f i c IgE an t ibod ies , adec l ine in a l l e rgen-spec i f i c IgE an t ibod ies , r i s e o fa l l e r g e n - s p e c i f i c I g A a n d I g G a n t i b o d i e s i n n a s a ls e c r e t i o n s , d e v e l o p me n t o f a l l e r g e n - s p e c i f i c s u p -p r e s s o r T c e ll s, d e c l i n e i n l y mp h o c y t e r e s p o n s i v e -ness to spec i f i c a l l e rgens , and in some pa t i en t sr e d u c t i o n o f i n v i t r o h i s t a mi n e r e l e a s e f r o m p e -r i p h e r a l b l o o d b a s o p h i l s w h e n s p e c i f i c a l l e r g e n i sa d d e d ? 6 I n a d d i t io n , o t h e r f i nd i n gs c o n s i s t e n t w i thp o s s i b l e i mmu n o l o g i c c h a n g e s i n c l u d e s u p p r e s s i o no f i mme d i a t e a n d l a t e n a s a l r e a c t i o n s a n d l a t eb r o n c h i a l r e a c t i o n s a f t e r a l l e r g e n c h a l l e n g e; r e d u c -t ion in con junc t iva l sens i t iv i ty ; suppress ion o f eo -s inoph i l migra t ion in to nasa l secre t ions a f t e r i n t ra -n a s a l a l l e r g e n c h a l l e n g e ; a n d r e d u c t i o n o fe o s i n o p h i l s , e o s i n o p h i l i c c h e mo t a c t i c f a c t o r , a n dn e u t r o p h i l c h e mo t a c t i c f a c t o r i n b r o n c h o a l v e o l a rl a v a g e f lu i d a f t e r s e a s o n a l e x p o s u r e t o b i r c h p o l l e nin pa t ien ts wi th as thm a. 22, 23

T h e r i s e i n I g G ( b l o c k i n g ) a n t i b o d i e s a s s o c i -a t e d w i t h a l l e r g e n i m m u n o t h e r a p y i s d o s e - d e -p e n d e n t a n d h a s b e e n s h o w n t o o c c u r w h e na b o u t 6 t o 1 2 ~ g o f A r a b a 1 , t h e m a j o r a l l e r g e ni n s h o r t r a g w e e d , h a s b e e n a d m i n i s t e r e d . 2z C o m -p a r a b l e d o s e s c a p a b l e o f c a u s in g a s i g n if i ca n tr i se i n I g G a n t i b o d i e s a r e 5 0 0 0 t o 2 5 , 00 0 p r o t e i nn i t r o g e n u n i t s o r a c o m p a r a b l e n u m b e r o f b i o -e q u i v a l e n t a l le r g y u n i ts ( B A U ) ( s e e P a r a m e t e ro n D i a g n o s t i c T e s t i n g f o r d e f i n i t i o n a n d d i s c u s -s i o n o f t h e r e l e v a n c e o f p r o t e i n n i t r o g e n u n i tsa n d B A U ) . W i t h c o n t i n u e d a l l e r g e n i m m u n o -t h e r a p y , a l l e r g e n - s p e c i f i c I g G l e v e l s c o n t i n u e t or i s e a n d t h e n p l a t e a u , z3 D e c l i n e i n a l l e r g e n -s p e c i f i c I g E o c c u r s a f t e r l o n g - t e r m a l l e r g e n i m -m u n o t h e r a p y , b u t n o t , in m o s t p a t i e n t s , t o a l e v e lt h a t r e s u l ts in t h e d i s a p p e a r a n c e o f i m m e d i a t ec u t a n e o u s r e a c t i v i t y ? 6

C o n s i d e r i n g t h e c o m p l e x i t y o f b o t h c o g n a t e( s p e ci f ic a n t i g e n r e c o g n i t i o n ) a n d n o n c o g n a t e( a mp l i f i c a t i o n mo l e c u l e s , e . g . , I L - 4 ) f a c t o r s i nI g E p r o d u c t i o n a n d t h e r o le o f p r o in f l a m m a t o r yc y t o k i n e s a n d a d h e s i o n m o l e c u l e s i n t h e t o t a la l l e r g i c r e s p o n s e , c l i n ic a l e f f i c a c y o f a l l e r g e ni m m u n o t h e r a p y c a n n o t y e t b e a t t r ib u t e d t o a

s i ng l e m e c h a n i s m . R e c e n t e x p e r i e n c e w i t h r a p id /r u s h f o r m s o f d e s e n s i ti z a t io n , b o t h f o r i n s e c tv e n o m a n d s e m i n a l p l a s m a i m m u n o t h e r a p y ,h a v e d e m o n s t r a t e d t h a t t r u e d e s e n s i t i z a t i o n m a yb e d e m o n s t r a t e d i n a b o u t 2 5% t o 3 0 % o f t r e a t e dp a t i e n t s ( i m m e d i a t e l y a f t e r t h e 2 - h o u r i m m u n i -z a t i o n s c h e d u l e ) . 4, 24 T h i s s t a t e o f d e c r e a s e d c e l lr e s p o n s i v e n e s s p e r s i s t s a s l o n g a s t h e i n j e c t i o n sa r e c o n t i n u e d o n a r e g u l a r s c h e d u l e .

A l t h o u g h t h e a m o u n t o f sp e c if i c I g G ( b l o c k i n ga n t i b o d y ) i s a g o o d i n d i c a ti o n o f t h e t o t a l a l l e r g e nd o s e d e l i v e r e d t o t h e p a t i e n t, o v e r a l l c o r r e l a t io n o fth i s m odal i ty w i th c l in i ca l e f f i cacy i s mod es t i nmos t c l in i ca l s i tua t ions , excep t perhaps fo r insec tv e n o m i mmu n o t h e r a p y . n A n t i - i d i o t y p i c a n t i b o d i e sh a v e a l s o b e e n d e mo n s t r a t e d i n p a t i e n t s r e c e i v i n ga l l e r g e n i mmu n o t h e r a p y , b u t t h e r e i s a s y e t n og o o d c o r r e l a t i o n w i t h t h e s e r e g u l a t o r y a n t i b o d i e san d clinical resu lts, z5-27

I n d u c t i o n o f p e r i p h e r a l T - c e ll t o le r a n c e a p p e a r st o b e a n o t h e r o f t h e a t t ra c t i v e h y p o t h e s e s , z~H i g h d o s e t o l e r a n c e c o u l d c a u s e a d e c r e a s e i ns p e c i f i c B - l y mp h o c y t e c e l l p o p u l a t i o n s . A n t i g e n -a n t i b o d y c o m p l e x e s w o u l d m o s t l i k e l y i n d u c et h i s t y p e o f t o l e r a n c e . T h i s h y p o t h e s i s i s c o n s i s -t e n t w i t h t h e r e c e n t d e m o n s t r a t i o n t h a t p r e -f o r m e d a n t i b o d y c o m p l e x e s ( i n a n t i b o d y e x c e s s )m a y b e e f f e c t i v e i n t h e t r e a t m e n t o f s o m e a l l e r -g i c d is e a s e s , z l H o w e v e r , f o r t h i s h y p o t h e s i s t o b ec r e d i b l e , i t w o u l d b e n e c e s s a r y t o d e m o n s t r a t et h a t B - c e l l m e m o r y c e l ls a r e c o m p l e t e l y d e l e t e d .L o w d o s e - t o l e r a n c e c o u l d i n v o l v e T - h e l p e r l y m -p h o c y t e s u b p o p u l a t i o n s , T - s u p p r e s s o r l y m p h o -c y t e s u b p o p u l a t i o n s , a n d / o r a n t i g e n - p r e s e n t i n gc e l l s , w h i c h i n c l u d e f o l l i c u l a r d e n d r i t i c c e l l s ,ma c r o p h a g e s , a n d B c e l l s . T - c e l l t o l e r a n c e a f -f e c t in g e i t h e r T - h e l p e r o r T - s u p p r e s s o r c e ll p o p -u l a t i o n s c o u l d i n d u c e a s t a t e o f a n e r g y b y a f f ec t -i n g t h e T - c e l l r e c e p t o r c o m p l e x a n d s e v e r a lo t h e r c o s t i m u l a t o r y a n t i g e n s i n T - c e l l m e m -b r a n e s . M a n y o f t h e c u r r e n t h y p o t h e s e s c o n c e r n -i n g a l l e r g e n i c p e p t i d e v a c c i n e s s u g g e s t t h a t p e -r i p h e r a l T - c e l l t o l e r a n c e o c c u r s i n t h i sma n ne r. Z0 . 21 A l t h o u g h i t h a s b e e n d e m o n s t r a t e dt h a t s u p p r e s s o r T - c e l l s u b p o p u l a t i o n s a r e i n -c r e a s e d a f t e r a l l e r g e n i m m u n o t h e r a p y , t h e c o r -re l a t ion wi th c l in i ca l e f f i cacy i s m od es t , zsR e c e n t l y , h o w e v e r , S e h o n e t a l 29 h a v e d e m o n -s t r a t e d t h a t s o l u b l e T - c el l s u p p r e s s o r f a c t o r s a r eh o m o l o g o u s w i t h t h e T - c e l l r e c e p t o r oL -[3 h e t -e r o d i m e r , t h e r e b y i m p l y i n g t h a t t h e s e s o l u b l ef a c t o r s c o u l d d o w n r e g u l a t e T - c e l l r e c e p t o r a c t i -va t ion by sp ec i f i c a l l e rge n , z9


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C O N D I T IO N S F O R W H I C H E F F E C T IV E N E S SO F L L ER G E N I M M U N O T H E R P Y H SB E EN D E M O N S T R T E Dl lergic rhini t isW e l l - c o n t r o l l e d c l i n i c a l s t u d i e s h a v e d e mo n -s t r a t e d t h a t a l l e r g e n i mmu n o t h e r a p y i s b e n e f i c i a l

i n t h e t r e a t me n t o f s e a s o n a l p o l l i n o s i s c a u s e d b yt rees (e .g . , b i rch , moun ta in cedar ) , g ras ses (e .g . ,t imothy , rye) , weeds (e .g . , ragweed) and in thet rea tm en t o f m old - ind uced rh in i t is (e .g. , Alterna-ria, Cladosporium sp p . ) 9 -34 Cl in i ca l s tud ies havea l s o d e mo n s t r a t e d t h e e f fi ca c y o f a l l e rg e n i mmu -no therapy in a l l e rg ic rh in i t i s caused by dus t mi t es(e.g., Dermatophagoides farinae, D. pteronyssinusand animal sensi t iv i ty (e.g . , cat , d o g ) . 35 3 8

s t h m aW e l l - c o n t r o l l e d s t u d i e s h a v e d e mo n s t r a t e d t h ee f fi c ac y o f a l l er g e n i m mu n o t h e r a p y i n t h e t r e a t -m en t of as thm a. 39-4~E a r l y c o n t r o l l e d s t u d i e s r e l i e dh e a v i l y o n s u b j e c t i v e d a t a t o d e mo n s t r a t e t h a tc l i n i c a l i mp r o v e me n t c o u l d O c c u r . 4 1 '4 2 M o r e r e -cen t ly , s ign i f i can t c l in i ca l improvement based ons y m p t o m s c or e s, m e d i c a t io n u s e , e m e r g e n c y r o o mvis i t s , and /o r pu lmonary func t ion t es t s has beend e mo n s t r a t e d i n p a t i e n t s w i t h p o l l e n - i n d u c e d a n dmo ld- indu ced as thma. 23,43-45 Stud ies have a l sod e m o n s t r a t e d t h e e f f ic a c y o f a l le r g e n i m mu n o t h e r -a p y in s o m e p a t i e n t s w i t h p e r e n n i a l a l l e r g ic a s t h m acaus ed by an imal s (e.g. , ca t , dog) and dus tmites.3~, 37, 38, 46, 47 W ith reg ar d to th e latte r, so m ec h a l l e n g e s t u d i e s s h o w t h a t b o t h s p e c i fi c a n d n o n -s p e c i f i c a i r w a y r e s p o n s i v e n e s s c a n b e a t t e n u a t e da f t e r a l l e rg e n i mm u n o t h e r a p y 5 8 ,4 9 T h e c l in i c alr e l e v a n c e o f th e s e f in d i ng s i n r e g a r d t o d u s t m i t e sand an imal s needs to be c l a r i f i ed in pa t i en t s wi thc o n t i n u e d e x p o s u r e a l l e r g e n .I nsec t hypersens i t i v i t y

A l l e r g e n i m n m n o t h e r a p y s h o u l d b e c o n s i d e r e df o r p a t i e n t s w h o h a v e e x p e r i e n c e d i n s e c t - i n d u c e dhypersens i t iv i ty reac t ions a f t e r exposure to insec ta l l e r g e n s i n t r o d u c e d t h r o u g h v a r i o u s r o u t e s ( e . g . ,i nha la t ion , i n j ec t ion) . The e f f icacy o f ven om imm u-n o t h e r a p y i n t h e t r e a t m e n t o f s ti n g in g i n s e c t s e n -s i ti v ity to hon eybe ds , ye l low j acke t s , h o rne t s , andw a s p s h a s b e e n w e l l d e m o n s t r a t e d ? 1 ,5 ~ I n a d d i -t ion , severa l s tud ies have demons t ra t ed the c l in i ca le f f e c t i v e n e s s o f i m m u n o t h e r a p y w i t h w h o l e - b o d ye x t r a c ts o f i mp o r t e d f i r e a n t i n p a t ie n t s w h o h a v eh a d s y s t e mi c r e a c t i o n s a f t e r i mp o r t e d f i r e a n ts tings?~, 52 Al l e rg en im m uno ther apy ma y be e f fec-t iv e i n p r e v e n t i n g r e a c t i o n s t o s o me t y p e s o f b i ti n g

insec t s as wel l . Fo r exam ple , pa t i en t s w i th a h i s to ryo f a n a p h y l a x i s a f t e r b i t e s f r o m t h e b l o o d - s u c k i n ga r t h r o p o d , Triatom a protracta , h a v e b e e n p r o -t e c t e d a g a i n s t r e a c t i o n s f r o m s u b s e q u e n t b i t e sa f t e r r e a c h i n g ma i n t e n a n c e l e v e ls o f Triatoma ex-t r a c t 53 ( s e e A n a p h y l a x i s P a r a m e t e r ) . Pa t i e n t s w h oh a v e e x p e r i e n c e d s y mp t o ms a f t e r e x p o s u r e t o i n -ha led insec t a l l e rgens (e .g . , cockroach , cadd i s f ly ,w h o l e - b o d y b e e a l le r g e n s ) ma y a ls o b e n e f i t f r o mi mm u n o t h e r a p y , s4C O N D I T I O N S F O R W H I C H E F F E C T IV E N E S SO F L L ER G E N I M M U N O T H E R P Y H S N O TB E E N P R O V E N

T h e r e a r e n o w e l l - c o n t r o l l e d s t u d i e s t h a t s u p -p o r t t h e u s e o f a l l e r g e n i m m u n o t h e r a p y f o r f o o dhypersens i t iv i ty .A l t h o u g h a l l e r g e n i m m u n o t h e r a p y c o u l d , t h e o -r e ti c a ll y , b e u s e f u l f o r t r e a t m e n t o f l i f e - th r e a t e n i n gf o o d - i n d u c e d a n a p h y l a x i s , t h e u s e o f a l l e r g e n i m-mu n o t h e r a p y f o r t h i s c o n d i t i o n s h o u l d b e c o n s i d -ered inves t iga t iona l a t t h i s t ime.

Da ta o n the e f fec t iveness o f a l le rgen imm unother -a p y i n th e m a n a g e m e n t o f s k in a n d mu c o u s m e m-bran e d i sease such as a top ic dermat it i s, u r t i car ia , andCandida vulv ova ginitis ar e co nflicting , s4a,55,56C O N S I D E R T IO N S F OR L L E R G E NI M M U N O T H E R P YA l l e r g e n i m m u n o t h e r a p y is a n e ff e c t iv e f o r m o ft r e a t me n t f o r ma n y a l l e r g i c p a t i e n t s p r o v i d e d t h e yh a v e u n d e r g o n e a n a p p r o p r i a t e a l l e rg y e v a lu a t i o n .T h e e x p e c t e d r e s p o n s e to a l l er g e n i m m u n o t h e r a p yi s a n t i g e n - sp e c i f ic a n d d e p e n d s o n p r o p e r i d e nt if i -c a t i o n a n d s e l e c t i o n o f c o m p o n e n t a l l e r g e n s o n th eb a s i s o f t h e p a t i e n t s h i s t o ry a n d d i a g n o s ti c t e s tres ults. 32

A e r o a l l e r g e n i m m u n o t h e r a p y s h o u l d b e c o n s id -e r e d f o r p a t i e n t s w h o h a v e s y mp t o ms o f a l l e r g i cr h i n i t i s a n d / o r a s t h ma a f t e r n a t u r a l e x p o s u r e t oa l l e rg e n s a n d w h o d e m o n s t r a t e s p e c if i c I g E a n t i-bo die s to rele van t al lergens . 9, 16, 32 Th e seve ri ty an dd u r a t i o n o f s y mp t o m s s h o u l d a ls o b e c o n s i d e r e d i na s s e s s i n g t h e n e e d f o r s p e c i f i c a l l e r g e n i mmu n o -t h e r a p y . Se v e r i t y o f s y mp t o ms c a n b e d e f i n e d b ys u b j e c t i v e , a s w e l l a s o b j e c t i v e , p a r a me t e r s . T i mel o s t f r o m w o r k , e me r g e n c y d e p a r t me n t o r p hy s i -c i an o f f ice v is it s, a nd r espo nse to con ven t iona lme d i c a t i o n s a r e i mp o r t a n t o b j e c t i v e i n d i c a t o r s o fsever i ty . Pa t i en t s wi th a l l e rg ic rh in i t i s who areu n a b l e t o s l e e p b e c a u s e o f s y m p t o m s o r w h o s ed a y t i me s y mp t o ms i n t e r f e r e w i t h t h e i r w o r k o rs c h o o l p e r f o r m a n c e s h o u l d b e c o n s i d e r e d c a n d i -


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dates for specific allergen immunotherapy. Theimpact of the patient s symptoms on quality of lifeand responsiveness to other forms of therapy, suchas allergen avoidance or medication, should alsobe considered. Unacceptable adverse effects ofmedications may also favor one s decision to initi-ate allergen immunotherapy. Coexisting medicalconditions should also be considered in the evalu-ation a pat ient who may be a candidate for allergenimmunotherapy. Patients with moderate or severeasthma and/or allergic rhinitis require a combinedaggressive regimen of allergen avoidance, pharma-cotherapy, and allergen immunotherapy (seeAsthma Parameters).Hymenoptera venom immunotherapy should beconsidered in patients who have a systemic ana-phylactic reaction after an insect sting and havedocumented IgE sensitivity to specific insect ven-om.

Patients who have completed a course of aller-gen immunotherapy and who are again havingsignificant symptoms may require reevaluationwith consideration of an additional course of spe-cific allergen immunotherapy.Ther e are insufficient data addressing the useof aeroallergen immunotherapy in preschoolchildren. Although there is some disagreementabout the role of allergen immunotherapy inchildren under the age of 5 years, there havebeen reports of effectiveness of allergen immu-not herapy in this age group. 41 The ref ore eachcase should be considered individually by weigh-ing the risks and the benefits. For example, thereis concern about the difficulty of communicatingwith young children with regard to risks associ-ated with immunotherapy.57 On the other hand,for children who have had a history of anaphy-laxis to stinging insects or have severe allergicdisease, the benefits of allergen immunotherapymay outweigh the risks.C O N T R O V E R S I L O R U N C L E RI N D I C T I O N S

There are no data to support allergen immuno-therapy as a treatment for non-IgE-mediatedsymptoms of rhinitis or asthma. Data generally donot support the efficacy of allergen immunother-apy with bacterial vaccines or the efficacy andsafety of urine injections, The need for continuedallergen immunotherapy should be reevaluated ifit was initiated on the basis of inconclusive orinadequate testing for allergen-specific IgE anti-bodies or if a beneficial response has not occurred.

Patients who are mentally or physically unable tocommunicate clearly with the allergist and patientswho have a history of noncompliance are fre-quently not good candidates for immunotherapy. Ifa patient cannot communicate clearly with thephysician, it will be difficult for the patient toreport signs and symptoms, especially early symp-toms, suggestive of systemic reactions.Immunotherapy in patients with major humoral orcellular immune defects must be considered withregard to the benefits and risks in the individualpatient. It must be remembered that concern aboutimmunotherapy in such patients is largely theoreticaland that immunotherapy may provide some relieffrom allergy symptoms in such individuals. I t shouldalso be remembered that administration of immuno-therapy to patients who may harbor bloodbornepathogens increases the risk of needle-stick injuriesto the persons administering the injections. Althoughconcern about the safety of allergen immunotherapyin patients with autoimmune disease or connectivetissue disease has been raised in the past, there is nosubstantive evidence that such treatment is harmfulin these diseases. 58, 59 Therefore the risks and bene-fits of allergen immunotherapy in patients with auto-immune or connective tissue disease must be as-sessed on an individual basis.S E L E C T IO N O F R E L E V N T L L E R G E N SIn choosing the components for a clinicallyrelevant extract, the physician should know localand regional aerobiology with regard to pollens,fungi, and indoor allergens (e.g., dust mites) andbe aware of potential allergens in the patient s ownenvironment. A knowledge of the allergenic bur-den facing a patient is useful in determiningwhether allergen immunotherapy should be initi-ated in addition to pharmacologic and environ-mental intervention. On the one hand, the omis-sion of clinically relevant allergens from anallergenic extract may contribute to decreasedeffectiveness of allergen immunotherapy. On theother hand, inclusion of all allergens to which IgEantibodies are present without establishing possi-ble clinical relevance can dilute the individualallergen content of the extract so that immuno-therapy will be ineffective. A patient s lifestyle mayproduce exposure to a wide variety of aeroaller-gens from different regions.

The most commonly used allergenic extracts arepollens of trees, grasses, and weeds, as well as moldspores, dust mites, animal allergens, and Hyme-noptera venoms. House dust extract is generally an


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inappropriate substitution for the house dust mitepreparation. 36In addition to recognizing the important aller-gens in a patient's environment, it is essential for

the allergist to be updated continually on newenvironmental antigens. This includes an aware-ness of newly introduced flora, which may haveincreased in number because of changes in soil,weather, or other factors; changes in or newlyrecognized insect (or mite) populations; changes inanimal allergen exposure; and the potential forsymptoms caused by other as yet undiscoveredallergens or their byproducts.Standardized allergenic extracts should be usedwhenever possible. These allergens have a definedpotency and are labeled with a common unit, theBAU, 6~ which is based on an official Food andDrug Administration protocol of skin test titration.Extracts that produce an identical skin response ata 1:5 million dilution are bioequivalent and as-signed a unitage of 100,000 BAU. Nonstandard-ized allergens are labeled by protein nitrogen unitsor weight by volume, but this does not reflect thepotency of the product, and therefore a safe andeffective dose of a single lot of nonstandardizedallergen cannot be generalized to another lot ofthe same nonstandardized product. Thus there isincreased danger of systemic reactions when trans-ferring immunotherapy from one medical facilityto another without reassessing the patient's sensi-tivity to allergenic materials that will be used forfuture immunotherapy in the new treatment cen-ter. Standardized allergens are generally availableat a comparatively higher concentration. They areprepared as aqueous, glycerinated, and freeze-dried formulations and are compatible for mixingwith nonstandardized products. Theoretically,there is less risk of adverse reactions with stan-dardized allergens because of greater predictabilityabout their potency.

L L E R G E N P O T E N C Y N D S T B I L IT YCommercial extracts are obta ined by allergists inconcentra ted forms (1:10 to 1:30 wt/vol). Oncereceived in the once, the potency of the extract isaffected by a number of factors. These include: (1)the passage of time, (2) storage temperature, (3)concentration, (4) relative volume of the storage vial,(5) the presence of proteolytic enzymes, and (6) the

presence of stabilizers and antibacterials. The rate ofpotency loss over time is influenced strongly by thesefactors separately and collectively.6x, 62To minimize the rate of potency loss, aqueous

extracts should be refrigerated at 4 ~ C. Potency ofconcentra ted extracts (1:10 to 1:100) under thisstorage condition is assumed to be constant andmaintained to the expiration date of the stockmaterial. If such extracts are removed from therefrigerator for short periods at frequen t intervals,as would occur with allergen immunotherapy, com-parative loss of potency over 1 year's span isminimal. On the other hand, if such extracts arekept at room temperature for extended periods,loss of potency is accelerated. Less concentratedextracts (1:1000 or more dilute) lose potency muchmore rapidly, especially when stored at room tem-perature, and should be replaced accordingly.The more concentrated extracts lose their po-tency less quickly. Lyophilization is used to main-tain the strength of the dry powder, but onceextracts are reconstituted, stabilizing agents suchas human serum albumin (0.03 ) are needed tomaintain potency. Stabilizers (human serum albu-min and glycerol) counteract the loss of potencywithin storage vials by preventing adsorption ofallergen on the inner surface of the glass vial.Stability of extracts is enhanced by lyophilizationand/or dilution of stock allergens (1:10 or 1:20) in50 glycerol. At this concentration, glycerol isirritating and therefore should be diluted furtherbefore immunotherapy administration. All di-luents should contain an antibacterial such asphenol.At present, data to support or reject the practiceof combining allergens in one extract (e.g., com-bining pollen and mold allergens) are lacking.63 Inaddition, pollen, mold, and mite allergens haveenzymatic activity, including both protease andsugar-cleaving enzymes. Mold and house dust ex-tracts may have greater proteolytic activity thanpollens. The relevance of these studies in terms ofmixing antigens in an allergenic extract has yet tobe proven.P R E C U T I O N S R E G R D I N G L L E R G E NI M M U N O T H E R P Y

Patients who are receiving [3-adrenergic-block-ing agents should generally not receive allergenimmunotherapy.64 However, when the patient re-ceiving a [3-blocker is at risk of a life-threateningreaction if allergen immunotherapy is not started,as would be the case in a patient with stinginginsect hypersensitivity, allergen immunotherapymight be indicated. This assumes that there is noacceptable medication that can be substituted forthe [3-blocker.


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1 8 Pra ct ice pa ra me te rs J ALLERGY CLIN IMMUNOLDECEMBER 1996

A l t e r n a t i v e s t o a l l e r g e n i mmu n o t h e r a p y s h o u l db e c o n s i d e r e d i n p a t i e n t s w i t h a n y me d i c a l c o n d i -t ion tha t reduces the ab i l i t y to su rv ive a sys t emica l le r g i c r e a c t io n : p a t i e n t s w h o h a v e m a r k e d l y c o m -p r o mi s e d l u n g f u n c t i o n ( e i t h e r a c u t e o r c h r o n i c ) ;p a t i e n t s w i t h p o o r l y c o n t r o l l e d a s t h ma ; p a t i e n t sw i t h u n s t a b l e a n g i na , r e c e n t my o c a r d i a l i n f ar c t io n ,o r s ign i f i can t a r rhy thmias ; pa t i en t s wi th uncon-t r o l l e d h y p e r t e n s i o n ; a n d p a t i e n t s w i t h f a i l u r e o f ama j o r o r g a n s y s t e m, s u c h a s r e n a l f a i l u r e .

T h e r e ma y b e e x t e n u a t i n g c i r c u ms t a n c e s i nw h i c h i m m u n o t h e r a p y m a y b e i n d i c a te d f o r ah igh- r i sk pa t i en t , bu t t he re l a t ive r i sks and benef i t smu s t b e c a r e f u l l y c o n s i d e r e d . A n e x a mp l e o f s u c ha s i t u a t i o n w o u l d b e a p a t i e n t w h o h a s h y p e r t e n -s ion tha t i s success fu l ly con t ro l l ed wi th a B-b locke rand wh o i s a l so sens it ive to s t ing ing insec t s . I f a f t e rc o n s u l t a t i o n w i t h t h e p h y s i c i a n ma n a g i n g t h e p a -t i en t s hy per t ens ion , i t is ag re ed tha t s topp in g theB-b lock er is no t in the p a t i en t s be s t i n t e res t , i t m ays t i l l b e n e c e s s a r y t o i n i t i a t e i mmu n o t h e r a p y w i t ht h e a p p r o p r i a t e v e n o m e x t r a c t .

A l l e r g e n i mmu n o t h e r a p y o r d i n a r i l y s h o u l d n o tb e i n i t i a t e d d u r i n g p r e g n a n c y , a l t h o u g h i t c a n a n dp r o b a b l y s h o u l d b e ma i n t a i n e d d u r i n g p r e g n a n c y ,p r o v i d e d t h e p a t i e n t i s t o l e r a t i n g t h e t h e r a p y w e l land has reached a dose o f ex t rac t su f f i c i en t t op r o v i d e s y m p t o ma t i c r e l i e f Y T h e r e i s t h e p o t e n t i a ltha t a sys t emic reac t ion to an in j ec t ion o f a l l e r -gen ic ex t rac t cou ld p ro du ce severe fe t a l hypox ia . 65I t i s a l so p o s s i b l e t h a t a s y s t e mi c r e a c t i o n c o u l dc a u s e u t e r i n e c o n t r a c t i o n s , l e a d i n g t o s p o n t a n e o u sa b o r t i o n o r p r e m a t u r e l a b or . 5s H o w e v e r , i m m u n o -t h e r a p y f o r l i f e - t h r e a t e n i n g d i s e a s e , s u c h a s a n a -p h y l a c t i c r e a c t i o n t o i n s e c t s ti ng s , ma y w a r r a n ti n i ti a ti o n o f i mm u n o t h e r a p y d u r i n g p r e g n a n c y .R IS K S S S O C I T E D W I T H L L E R G E NI M M U N O T H E R P Y

T h e ma j o r r i sk o f a l l e r g e n i mm u n o t h e r a p y i sa n a p h y l a x i s , w h i c h i n e x t r e me l y r a r e c a s e s c a n b ef a t a l d e s p i t e o p t i ma l ma n a g e me n t . T h e r e f o r e a l -l e r g en i m m u n o t h e r a p y s h o u l d b e a d m i n i st e r e d u n -d e r t h e s u p e r v i s i o n o f a n a p p r o p r i a t e l y t r a i n e dp h y s i c i a n . T h e h e a l t h c a r e p r o v i d e r w h o a d mi n i s -t e r s i mmu n o t h e r a p y i n j e c t i o n s s h o u l d b e a b l e t or e c o g n i z e e a r l y s y m p t o ms a n d s ig n s o f a n a p h y la x i sa n d a d mi n i s t e r e m e r g e n c y me d i c a t i o n s i f n e c e s -s a ry . I n a d d it i o n , e v e r y e f f o r t s h o u l d b e ma d e t op r e v e n t a n a p h y l a c t i c r e a c t i o n s c a u s e d b y a l l e r g e ni mmu n o t h e r a p y . T h i s i n c l u d e s : ( 1 ) a d j u s t me n t o fe x t r a c t d o s a g e o f a l l e r g e n i mm u n o t h e r a p y i f s y mp -t o ms o f a n a p h y l a x i s o c c u r a n d a l l e r g e n i mmu n o -

t h e r a p y i s c o n t i n u e d ; ( 2 ) p o s s i b l e a d j u s t me n t o fex t rac t dosa ge i f l a rge loca l reac t ions occur ; (3 ) useof more d i lu t e in i t i a l ex t rac t s in se l ec t ed pa t i en t sw h o a p p e a r t o h a v e i n c r e a s e d s e n si ti v it y o n t h ebas i s o f h i s to ry and /o r resu l t s o f t es t s fo r spec i f i cIgE an t ibod ies ; (4 ) ins t ruc t ion fo r pa t i en t s to wai tin the phys ic i ans s o f f i ce fo r a t l eas t 20 m inu tesa f t e r a n i mmu n o t h e r a p y i n j e c t i o n a n d i n s p e c t i o nof the in j ec t ion s i t e befo re pa t i en t s l eave ; (5 )e v a l u a t i o n o f p a t i e n t s b e f o r e t h e n e x t i mmu n o -t h e r a p y i n j e c ti o n w i t h r e g a r d t o l o c a l r e a c ti o n s o rs y s t e mi c s y mp t o ms o c c u r r i n g l a t e r t h a n 2 0 t o 3 0mi n u t e s a f t e r t h e i n j e c t i o n ( i n o r d e r t o d o t h i sef fec t ive ly , educa t ion o f the pa t i en t i s es sen t i a l ) ;( 6 ) a s s e s sme n t o f th e g e n e r a l m e d i c a l c o n d i t io n o fthe pa t i en t a t t he t im e o f the in j ec t ion (e .g .,p r e s e n c e o f a n u p p e r r e s p i r a t o r y t r a c t i n f e c t i o n o ra s t h ma e x a c e r b a t i o n ) ; ( 7 ) p r o c e d u r e s t o a v o i dc le r i ca l o r nurs ing e r ro rs ; and (8 ) recogn i t ion tha td o s a g e a d j u s t me n t s m a y b e n e c e s s a r y w i t h n e w l ypre par ed ex t rac t s , i f t he pa t i en t has h ad a s ign if i-c a n t i n t e r r u p t i o n i n t h e i mmu n o t h e r a p y s c h e d u l e ,o r i f t h e r e a r e m a r k e d c h a n g e s i n a l l e r g e n e x p o -su re (e .g . , du r ing the a l l e rgen season) .

Be f o r e a l l e r g e n i mmu n o t h e r a p y i s c h o s e n a s at r e a t me n t , i t i s i n c u mb e n t o n t h e p h y s i c i a n t oe d u c a t e p a t i e n t s w i t h r e g a r d t o t h e r i s k s a n db e n e f i t s o f i m m u n o t h e r a p y a n d m e t h o d s f o r m i n -imiz ing these r i sks . The pa t i en t shou ld a l so bei n f o r me d t h a t d e s p i t e p r o p e r a t t e n t i o n t o a l l t h e s er is k s, r e a c t i o n s m a y o c c u r w i t h o u t p r e c e d i n g w a r n -ing s igns o r symptoms .

M o n i t o r i n g o f p a t ie n t s r e c e i v in g a l l e rg e n i m mu -n o t h e r a p y i s i mp o r t a n t t o ma x i mi z e t h e e f f i c a c ya n d s a f e t y o f t h is f o r m o f t h e ra p y . Sa f e t y mo n i t o r -i n g s h o u l d b e d e s i g n e d t o r e d u c e t h e r i s k o fr e a c t i o n s f r o m a l l e r g e n i mmu n o t h e r a p y . Su c hmo n i t o r i n g i n c l u d e s a s s e s s me n t o f t h e p a t i e n t scond i t ion , as wel l as loca l and sys t emic reac t ionsf r o m i m m u n o t h e r a p y .

L o c a l r e a c t i o n s , i n c l u d i n g s u b c u t a n e o u s n o d -u les , a re def ined as reac t ions occur r ing in theimmedia te v i c in i ty o f the in j ec t ion s i t e . Loca lr e a c t i o n s c a n b e s u b d i v i d e d i n t o t h o s e t h a t o c c u rwi th in 20 to 30 minu tes a f t e r t he in j ec t ion (dur ingt h e p e r i o d o f t i me t h a t t h e p a t i e n t i s b e i n g o b -served in a c l in i ca l se t t ing ) and those tha t occurl a t e r t h a n 3 0 mi n u t e s a f t e r t h e i n je c t i o n b u t b e f o r ethe nex t in j ec t ion . I f t he pa t i en t expe r i ences l a rgel o c a l r e a c t io n s , a d j u s t me n t o f e x t r a c t d o s a g es h o u l d b e c o n s i d e r e d .

Sy s t e mi c r e a c t i o n s a r e d e f i n e d a s f o c a l o r g e n -e r a l i z e d s y mp t o ms a n d / o r s i g n s o c c u r r i n g d i s t a n t


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J A LL ER G Y C LIN IM M U NO L P r a c t i c e p a r a m e t e r s 1 0 0 9VOLUME 98 NUMBER 6 PART 1

f r o m t h e i n j e ct i o n s i te . Sy s t e mi c r e a c t i o n s m a ybeg in wi th in 20 to 30 minu tes a f t e r t he in j ec t ion o rl a t e r . I f a sys t emic reac t ion occurs , reeva lua t ion o ft h e p a t i e n t ' s i mmu n o t h e r a p y p r o g r a m i s i n d i c a t e d .

I n e x c e p t i o n a l c a s e s i n w h i c h a l l e rg e n i mm u n o -t h e r a p y c a n n o t b e a d m i n i s t e r e d i n a me d i c a l f a c il -i ty , v e r y c a r e f u l c o n s i d e r a t i o n o f p o t e n t i a l b e n e f i t sa n d r i s k s o f a t - h o me a d mi n i s t r a t i o n o f a l l e r g e n i cex t rac t t herapy mus t be made on an ind iv idua l pa-t ient basis . I t should be noted, however, that theFood and Drug Admin i s t ra t ion 's package inser t t ha taccompanies al l al lergenic extracts impl ies that al -lergy inject ions should be given in a cl inical set t ingunde r the superv i s ion o f a phys ic i an wi th the p a t i en twai ting a t leas t 20 min utes af ter the injection. Pa-t i en t s who are a t g rea te r r i sk o f reac t ions f romi mm u n o t h e r a p y m a y n e e d t o w a i t lo n g e r.M O N I T O R I N G O F C L I N IC L E F F IC C Y

The on ly c r i t e r ion fo r as sessment o f c l in i ca le f f i cacy o f aeroa l l e rgen immunotherapy i s c l in i ca leva lua t ion . Cl in i ca l eva lua t ion cou ld inc lude sub-j e c t iv e p a r a m e t e r s ( e .g . , g l o b a l a s s e s sme n t , s y mp -tom s) o r ob jec t ive par am eters (e .g ., resu l t s o fp u l mo n a r y f u n c t i o n t e s t s , me d i c a t i o n u s e ) .

D u r i n g t h e i n it ia l t r e a t me n t p h a s e o f i n c r e me n -t a l i n c r e a s e s i n d o s a g e , p a t i e n t s ma y n e e d t o b es e e n a t f r e q u e n t i n t e r v a l s . O n c e t h e p a t i e n t w i t h -o u t c o mp l i c a t i o n s h a s r e a c h e d a ma i n t e n a n c edosage l eve l , fo l low-up v i s i t s wi th the spec ia l i s te v e r y 6 t o 1 2 mo n t h s m a y b e a d e q u a t e .T h e i mme d i a t e a n d l a t e s k i n t e s t r e a c t i o n s t oa e r o a l l e r g e n s ma y d e c r e a s e , b u t o n l y a f t e r a l o n gp e r i o d o f i m m u n o t h e r a p y . M o r e o v e r , t h e s k i n t es tr e s p o n s e t o a e r o a l l e r g e n s a f t e r a p e r i o d o f i mmu -n o t h e r a p y i s v a r i a b l e a n d d o e s n o t n e c e s s a r i l yc o r r e l a t e w i t h c l i n i c a l r e s p o n s e . T h e r e f o r e s k i nt e s ti n g a l o n e ma y n o t b e v a l u a b l e i n a s s e s si n g t h ee t f i cacy o f immunotherapy in ind iv idua l pa t i en t s .A s a r e s u l t , f r e q u e n t s k i n t e s t i n g s h o u l d n o t b ee n c o u r a g e d , a l t h o u g h a r e p e t i t i o n o f s k in t e s ti n g a t3 - to 5 -year in t e rva l s may he lp to as sess thepat ient 's cl in ical s tatus .

The c r i t e r i a fo r moni to r ing s t ing ing insec t im-mu n o t h e r a p y a r e n o t w e l l e s t a b l i s h e d . I n t h e a b -s e n c e o f a r e s p o n s e f r o m a n a t u r a l s t i n g , r e c e n td a t a s u g g e s t t h a t a f t e r a 5 - y e a r p e r i o d o f v e n o mi mmu n o t h e r a p y , t h e p a t i e n t i s a t n o g r e a t e r r i s kthan the gene ra l popu la t ion . 1~ W hi le awai t ingconf i rmat ion o f these da ta , i t may be appropr i a t e toevaluate the pat ient wi th tes t ing for specif ic IgEan t ibod ies . Thre e c r i te r i a ( two imm unolog ic and on ed e p e n d e n t o n t h e d u r a ti o n o f t h e r a py ) h a v e b e e n

p r o p o s e d a s g u i de l in e s f o r c e s s a ti o n o f v e n o m i mmu -nothera py. T hes e are loss of skin tes t reactivity , adecrease in t i te r s o f se rum venom-spec i f i c IgE an t i-bod ies to undetec tab le l eve l s , and a f in i t e per iod o ft reatment ( i .e . , 3 to 5 years) . This lat ter cr i ter ion isno t in f luenced by sk in t es t reac tMty o r se rum an t i -bod y t i te r .

L L ER G E N I M M U N O T H E R P Y I N R E M O T EH E L T H F C I L IT I E S

Because of convenience and logis t ic factors , al -lergy extracts are ofte n prep are d b y special is ts fo radminis t rat ion in the off ices of primary care physi-cians or specialists or other health service facili t ies,which can ensure that a physician wi l l be able torespond wi th in 2 to 3 minu tes i f needed . When th i sservice is un der take n by the al lergy special is t, specialat tent ion by the al lergy specialist shou ld be given to:(1 ) p roper iden t if i ca tion o f each v ial o r con ta iner o fextract, including nam e of pat ient , al lergen co nten tand p ropor t ions , s t reng ths (d i lu t ions ) , and da tes o fexp i ra t ion o f each ingred ien t ( in mos t cases theexp i ra t ion da te shou ld no t exceed 1 year bu t m oredi lute extracts expire more rapidly); (2) precise in-s t ruct ions regarding the schedule of al lergy injec-t ions ; (3 ) emphas i s on the abso lu te requ i rement o fan o f f i ce observa t ion per iod o f a t l eas t 20 minu tesaf t e r each in j ec t ion (pa t i en t s who do no t heed th i sadvice should be refer red b ack to the al lergy special-i s t ) ; (4 ) adequate descr ip t ion o f immedia te and l a t elocal and systemic react ions; (5) special ins t ruct ionon ho w to m odi fy the do sage schedu le i f a reac t ionoccurs o r i f t he pa t i en t d oes no t adh ere to thereco m me nde d schedu le ; and (6 ) p rov i s ion o f a li st o fp recau t ions fo r immunotherapy inc lud ing recen theavy a l l e rgen exposure , con com i tan t use o f [3 -b lock-ing drugs , acu te cl inical f lares of as thma, up pe rrespiratory t ract infect ions wi th fever, or seriousc o n c u r r e n t i l l n e s s e s . I n m o s t c a s e s t h e a l l e r g ys p e c i a l i s t w i l l p r e f e r t o a d mi n i s t e r t h e f i r s t i n j e c -t i o n o f a n e w e x t r a c t v i a l i n h i s o r h e r f a c i l i t y .T h e a l le r g y s p e c ia l i st s h o u l d b e c o n t a c t e d i f t h ep a t i e n t b e c o m e s p r e g n a n t b e f o r e s t a r t i n g o rw h i l e r e c e i v i n g i m m u n o t h e r a p y .

In add i t ion to the these p recau t ions , t he phys ic i anresponsible for adminis tering the al lergenic extractshou ld be in fo rme d by the a l l ergy spec ia l is t abou t thet y p e o f e me r g e n c y t r e a t me n t t h a t ma y b e n e c e s s a r yin the event that a l i fe- threatening, anaphylact icreac t ion occurs . Ep inephr ine (1 :1000) shou ld beava i l ab le fo r immedia te admin i s t ra t ion , and dos inginst ruct ions for i t s use sh ould b e given. Provis ions formain ta in ing an open a i rway shou ld be in p l ace .


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1 1 P r a c t i c e p a r a m e t e r s J A L LE R GY C L IN IM M U N O LDECEMBER 996

M e d i c a l e q u i p m e n t a n d s u p p l i e s fo r t r e a t m e n t o fs h o c k s h o u l d b e i n t h e o f fi c e. F i n a l l y , t h e p h y s i c i a n ,w i t h t h e a i d o f m e d i c a l s t af f, s h o u l d b e c o m p e t e n t i nt h e t e c h n i q u e o f c a r d i o p u l m o n a r y r e s u s c it a t io n .

R E F E R E N C E S1 . Noon L , Can tab BC. P rophy lac t ic inocu la t ion aga ins t hayfever. Lancet 1911;1:1572-4.2 . F ree ma n J . Rus h inocu la t ion . Lance t 1930;1 :744-7 .3 . v a n d e r Z w a n J C , F l i n t e rm a n J , J a n k o w s k i I G , K e r c k h a e r t

JA. Hyposens i t iza t ion to wasp venom in s ix hours . B rMed J 1983;287:1329-31.4 . B e r n s t e i n D I , M i t t m a n R J , K a g e n S L , K o r b e e L , E n r i o n e

M, Berns te in IL . C l in ica l and immunolog ic s tud ies o fr a p i d v e n o m i m m u n o t h e r a p y i n H y m e n o p t e r a - s e n s i t i v epa t ien ts . J A l le rgy C l in Imm unol 1989;84:951-9 .

5 . B i r n b a u m J , C a r p a in e D , V e r v l o e t D . R a p i d H y m e n o p -t e r a v e n o m i m m u n o t h e r a p y : c o m p a r a t i v e s a f e t y o f t h r e eprotocols. Clin Exp Allergy 1993;23:226-30.

6 . Berns te in JA, Kagen SL , Berns te in DI , Berns te in IL .R a p i d v e n o m i m m u n o t h e r a p y i s s a f e fo r r o u t i n e u s e i n th et rea tm en t o f pa t ien ts wi th Hy me nop te ra anaphy lax is . A nnAllergy 1994;73:423-8.

7 . B e r n s t e i n J A , H e r d A Z , B e r n s t e i n D I , K o r b e e L , B e r n -s te in IL . Eva lu a t ion and t re a tm en t o f loca l ized vag ina li m m u n o g l o b u l i n E - m e d i a t e d h y p e r s e n s i t i v i t y t o h u m a nsemina l p lasma . Obs te t Gyneco l 1993 ;82 :667-73 .

8 . B o u s q u e t J , H e j j a o u i A , D h i v e r t H , C l a u z e l A M , M i c h e lF B . I m m u n o t h e r a p y w i t h a s t a n d a r d i z e d Dermatophagoides pteronyssinus e x t r a c t . I I I . S y s t e m i c r e a c t i o n s d u r -i n g t h e r u s h p r o t o c o l i n p a t i e n t s s u f f e ri n g f r o m a s t h m a .J Al le r gy C l in Imm uno l 1989 ;83 :797-802 .

9 . I m m u n o t h e r a p y o f I g E - m e d i a t e d d i so r d e rs . G r e e n b e r g e rPA, ed i to r . Immunology and a l le rgy c l in ics o f Nor thAmer ica . Ph i lade lph ia : WB Saunders 1992 ;12 :1 -203 .10 . M osbech H, O s te rba l le O. Does the e f fec t o f immunother -

apy last after termination of treatment? Allergy 1988;43:523-8.11 . R e ism an R E . In sec t s tings . N En g l J M ed 1994;331:523-7 .12 . Love less MH. Repo s i to ry imm uniza t ion in po l len a l le rgy .J Immunol 1957;79:68-79.1 3 . P e c k H M , W o o d h o u r A F , M e t z g e r D P , M c K i n n e y S E ,

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