Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety

VOLUME 89 NUMBFR 2

43. Thompson PM, McLachlan SM, Pa&es A, Clark F, Howe1 D, Smith BR. The IgG subclass distribution of thyroglobulin antibody synthesize in culture. Stand J Immunol 1983;18: 123-9. 44. Anderson BR, Terry WD. Gamma GCglobulin antibody causing inhibition of clotting factor VIII. Nature 1968;217:174-5. 45. Bore1 Y. Isologous IgG-induced immunologic tolerance to haptens: a model of self versus non-self recognition. Transplant Rev 19?6;31:3-21.

46. Lee WY, Sebon AI-I. Suppression of reaginic ;intihodies. lmmunol Rev 1978;41:200-47. 47. Bernstein IL, Michael JG, Malkiel S. Sweet LC. Bracken RG. Immunoregulatory function of specific IgG. II. Clinical evaluation of combined active and passive Immunotherapy. Int Arch Allergy Appl Immunol 1979;58:30-7. 48. Tamir R, Castracane JM, Roclclin RE. Generation of suppressor cells in atopic patients during immunotherapy that modulate IgE synthesis. J ALLERGY CLIN IMMIJE~OI 19X7.‘YSL’i X

w jacket venom is Y efficacy and safety Ulrich Miiller, Bern,

Switzerland,

MD,* Arthur

Helbling,

and New Orleans,

MD,**

and Emanuel

WrchWd,*

MD

La.

Venom immunotherapy (VIT) for Hymenoptera allergy is accepted as safe and effective, However, widely varying success rates and frequencies of side effects are reported. Dtrerences between various Hymenoptera species could account for these diverging results. We therefore analyzed 205 patients with a history of systemic allergic reactions to either honeybee (148 patients) or yellow jacket stings (57 patients) during VIT. All patients had a positive skin test to the respective venom before VIT, were monitored for side effects of VIT, and submitted to N sting challenge while they were receiving VIT. Patients with honeybee-venom allergy had a higher sensitivi@ in both skin tests (p < 0.05) and RAST (p < 0.001) than patients with yellow jacket-venom allergy. They developed systemic side effects to VIT injections sign$cantly more often (41% versus 25%; p < 0.01) and also reacted more frequently to the sting challenge (2.?% versus 9%; p < 0.01) than patients with yellow jacket-venom allergy. We conclude that results obtained from studies on the allergy to one Hymenoptera venom cannot be extrapolated to allergies to other Hymenoptera venoms. (J ALLERGY CLIN IMMUNOL 1992;89:529-35.) Key words: Hymenoptera-sting immunotherapy

allergy, honeybee venom, yellow jacket venom, venom

VIT is accepted as a safe and effective treatment for patients with allergic SRs after Hymenoptera stings. I-3 However, widely varying success rates are reported from different centers. According to a CH

From tbe *Medical Division, Zieglerspital, Bern, Switzerland, **Division of Clinical Immunology and Allergy, Tulane versity School of Medicine, New Orleans, La. Received for publication Feb. 21, 1991. Revised Aug. 21, 1991. Accepted for publication Sept. 4, 1991. Reprint requests: Ulrich R. Miiller, MD, Medical Division, glerspital, CH-3007 Bern, Switzerland. l/1/33620

and Uni-

Abbreviations VIT:

SE: SSE: OSE: HB: YJ: HBV:

Zie-

YJV: EPC: CH: SR:

used

immunotherapy Systemic allergic side effects Subjective SE Objective SE Honeybee Yellow jacket (Vespula sp)

Venom

Honeybee

venom

Yellow jacket venom End point concentration Sting chaIlenge Systemic reaction J 529

530

Miiller

TABLE

J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1992

et al.

I. Clinical

Parameter

HBV

No. of pts Mean age ? SD (raw) M F Severity of SR* Grade II Grade III Grade IV Duration of VIT to CH in months + SD bw)

Immunotherapy

data of the patients allergy

148 32.4

+ 13.38 (8-71) 98 (66) 50 (34)

14 (19) 74 (SO) 60 (41) 46.85t k 33.45 (lt-168)

YJV

allergy

51 34.37 k (10-64)

13.05

28 (49) 29 (51) 7 (13) 31 (54) 19 (33) 60.16 r 21.3 (34-121)

Pfs, Patients. *Miiller” and Mueller? grade I, urticaria, itching, malaise; grade II, any of the above plus two or more of the following: angioedema, constriction in chest, nausea, vomiting, diarrhea, abdominal pain, or dizziness; grade III, any of the above plus two or more of the following: dyspnea, wheezing, stridor, dysphagia, dysarthria, or hoarseness; grade IV, any of the above plus two or more of the following: fall in blood pressure, collapse, loss of consciousness, incontinence, or cyanosis. tEarly CH in 36 beekeepers.

protocol

VIT was started by either a rush protocol (56 patients receiving HBV and 21 receiving YJV venom) with four daily injections, reaching the maintenance dose of 100 kg in 3 to 5 days, or by a conventional protocol (92 patients receiving HBV and 36 receiving YJV venom) with weekly sessions, reaching the maintenance dose of 100 p,g after 12 weeks as a rule. In beekeepers and in patients with an insufficient increase of venom-specific IgG to <3 *g/ml during the first 3 months of VIT,” the maintenance dose was increased to 200 pg. This finding was the case in 29 patients receiving HB and in two patients receiving YJ WT. Venoms for immunotherapy were obtained from Pharmacia AB, Uppsala, Sweden. The “European mix” of YJV contains venoms from V. germanica and V. vulgaris only and is thus different from the “American mix,” which contains venoms of four other Vespula sp in addition.

Recording

of SEs

SEs were recorded during the initial phase of VIT until the maintenance dose was reached. All patients were observed for at least 30 minutes after each injection. SEs were classified as local only, SSE (heat sensation, headache, nausea, fear, tightness of chest, dizziness, etc.) and OSE (flush, u&aria, angioedema, vomiting, diarrhea, wheezing, cough, drop in blood pressure, etc.).

CH

during VIT, full protection, as indicated by the absence of systemic allergic symptoms after CH during VIT, is reported in nearly 100% by some authors4-7 but only in 70% to 80% by other authors.*-l1 The incidence of SE during VIT also varies greatly. Some authors report SE in ~5% of the patients receiving VIT3x6. 12, 13; other authors report SE in up to 50% and more

9, 10, 14-16

Analysis of these widely diverging results suggests that, besides differences in the treatment protocol, conventional, clustered, or rush,4’ “3 I7 and the r,opulation treated, age and severity of previous reaction, 17-lg the species of venom used for VIT may be

important.

To investigate further this possibility,

we followed 205 patients with a history of severe SRs to Hymenoptera stings during VIT and observed the

incidence of SE and the reaction to a CH in relation to the culprit insect species. MATERIAL Patients

AND METHODS

Two hundred five patients with a history of severe SRs to Hymenoptera stings were included in the study. Honeybees (Apis mellifera) were the responsible insects in 148 patients and yellow jackets (Vespula sp) in 57 patients. All patients had positive skin tests and/or RAST results with the respective venoms before VIT. Patient data are presented in Table I.

HBs for CH were obtained from the Swiss Institute for Agricultural Research in Bern. Vespula nests were collected by the local fire brigade. Only V. germanica and V. vulgaris were used for CH. The CH was done at the intensive care unit with the patient connected to an ECG monitor and an intravenous infusion running. The insects were applied to the volar forearm. The stinger was removed from HBs without squeezing exactly 1 minute after the bee had stung. In vespids who do not usually loose the stinger during a CH, the abdomen was pressed against the underlying skin for 1 minute after the insect had stung. All patients were observed for 2 hours after the CH. Reactions to the challenge were classified as local only, subjective systemic and objective systemic. CHs with the HB were performed early, 1 to 12 months after starting VIT, in 36 heavily exposed bee-venom allergic individuals, such as beekeepers and their family members, farmers, or gardeners. All individuals had tolerated the maintenance dose of 100 wg at least three times before the challenge was done. No early CHs were done in YJV-allergic patients. In these and all other HBV-sensitive individuals, the CH was performed after at least 3 years of VIT to decide whether this treatment could be stopped.

Skin tests Intracutaneous skin tests with HBV and YJV were performed as described previously.” The volume of 0.02 ml of solution containing lo-“, 10m6, lo-“, and lo-’ gm/L was injected intracutaneously in the volar side of tbe forearm. The test was considered positive when a wheal of at least 5 mm in diameter with erythema was observed after 15 minutes. The lowest concentration resulting in such a

VOLUME 89 NUMBER 2

Bee and

Skin

tests

yellow

jacket

venom

differences

531

before treatment p ( 0.05

x2 = 8.01

n negative

10-6

IO-8

% of patients 100 r

!

Skin

80 k

tests before chaltenge x2 - 17.49 p ( 0.01

I

--

60

40

I I t

20

0 Negattve

10-3

10-4

10-6

10-8

skin test EPC in g/L m

BV-allergy

m

YV-allergy

RG. 1. Skin tests in HBV- and YJV-allergic patients. Both before ViT and before CH, skin sensitivity as measured by EPC is significantly higher in HBV-allergic patients. reaction is considered the EPC. Venoms for skin testing were supplied by Pharmacia AB. Spedfic

IgE antibodies

HBV- and YJV-specific serum-IgE antibodies were estimated by the commercially available Phadezym RAST (PharmaciaAB). The test was performed according to the recommendations of the manufacturer. RAST values are listed in RAST classesfrom 0 to 4. Stetistial

anelysis

The groups of HBV- and YJV-allergic patients were compared regarding the incidence of allergic SEs to VIT, the

reaction to the CH, as well as the results of kin tests and RAST by contingency-table analysisx2 test. RESULTS Skin tests The distribution of EPC in intmxitmeous skin tests with HBV and YJV before starting VIT md b&m CH is illustrated in Fig. 1. Patients w&b HW aIl@rgy had a higher skin test sensitivity to HW thm patients with YJV allergy to YJV, both before VIT (p < 0.05) and before the CH (p < 0.05). Skin test sensitivity decreased significantly during VIT in both groups.

532

Miiller

J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1992

et al.

% of patients 80

RAST before treatment

X2 = 37.83

p < 0.001

60 46

% of patients 100

RAST before challenge X2 = 24.3 p < 0.001

80

60

40

2c

, -

‘1

10

J@z?,, 2

CI-

1

0

2

1

3

0

4

RAST -class m

BV-allergy

FIG. 2. RAST in HBV- and YJV-allergic patients. significantly higher in HBV-allergic patients.

Specific

IgE

The distribution of RAST classes before VIT and before CH is illustrated in Fig. 2. Patients with HBV allergy had significantly higher serum levels of HBV IgE than patients with YJV allergy to YJV, both before VIT and before CH. RAST levels decreased significantly in both groups during VIT.

m Both

YV-allergy before

VIT and

before

CH, specific

IgE is

SEs

The incidence of SEs in the two treatment groups is presented in Table II. Although SSEswere observed with equal frequency, OSEs were significantly more often observed durmg VIT with HBV (p < 0.01). Four of the 29 patients (14%) receiving a maintetrance dose of 200 pg of HBV developed OSE, and

Bee and yellow jacket venom

VOLUME 89 NUMBER ?

TABLE 111.CH with the offending

insect ---__-_-

TABLE II. SEs of VIT VIT

Type

None or local only SSE OSE Total

CH with ----YJV (%I

Reaction

Local only SSE OSE Total

88 (59) 43 (75) 12 (21) 29 (20) 31 (21) 2 (4) 148 57 x’ = 9.46;~ < 0.01

rates of VIT according

Author

Gillman et a1.8 Przybilla et al. I0 Mi.iller et al.* Golden et al.J Mosbech et al.” Nataf et al.’ Miiller et al.* *This

with

HBV (%I

of SE

TABLE IV. Success

diffar-ences

HBV Mainly HBV HBV Mainly YJV YJV Mainly YJV YJV

-.-~.__ -__.ll---

HBV (%I

YJV (o/o)

114 (77) 52 (91 j 16 (11) 4 (7) 18 (12) i 12, 5; 148 x2 = 13.61: p <: u.01 --_.. .-.lll_

to CHs

Venom

533

-.---No.

challenged

18 157 148 143 19 14 57

No.

with

react&on

(%I

3 (22) 3.3 (2 I ) 34 (-5) ,.I 4 (3) 0 (0) 0 (0) 5 (9) .-_-.___-_.___-

study.

six patients (2 I %) developed SSE. For the 119 HBVallergic patients receiving a maintenance dose of 100 kg, the respective data are 26 (22%) with OSE and 23 patients (19%) with SSE. The difference between patients receiving a high and patients receiving a low maintenance dose regarding incidence of SE is not significant. SEs were observed somewhat, but not significantly, more often in women. The incidence for VIT with HBV was 38% in male and 46% in female patients. The incidence for patients receiving VIT with YJV was 25% for male and 29% for female patients. CH

The results of the CH are presented in Table III. None of the observed SRs to the CH were threatening, and all SRs were easily managed by treatment with either antihistamines, intravenously, or adrenaline, subcutaneously, or by inhalation. Objective symptoms: HB CH, 12%; YJ CH, 2%; subjective symptoms: HB CH, 11%; YJ CH, 7%, were observed significantly more often after the CH with the HB. An SR to the CH was observed in three of 29 (10%) HBV-allergic patients receiving a maintenance dose of 200 p,g and in 31 of 119 (25%) of patients receiving a maintenance dose of 100 pg. This difference is not

significant (p < 0.1). SRs to the CH were observed with similar frequency in both sexes; 23% of the male and 22% of the female patients reacted to the CH with the HB and 7% of the male and 10% of the female patients reacted to the.,CH with a YJ. Finally, SRs to the CH were observed in six of 36 (17%) early MB CHs and in 28 of 112 (25%) late HB CHs DISCUSSW Several authors have indicated differences in the tolerance experienced between various Hymenoptera venoms during VIT.14, 17,‘I. a’ Considerably varying success rates of VIT, as judged by the CH, have been published4-‘” and are presented in Table IV. These differences may, among other reasons. be explained by the fact that populations with allergies to different Hymenoptera venoms were studied. The current investigation with 205 patients receiving VIT with either HBV or YJV confirms these observations. SEs were observed significantly more often during VIT with HBV, and these patients reacted also significantly more often to the challenge during maintenance VIT. The reason for these differences is not clear. In the following discussion, wc analyze some of the possible explanations.

534

Miiller

Differences Table I)

J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1992

et al.

in the populations

studied

(see

The distribution of age, the severity of the last SR before VIT, and of the treatment protocol (rush versus conventional) was comparable in the two groups and can thus not account for the observed differences regarding safety and efficacy. There is a predominance of male patients with HBV allergy, whereas the sex distribution is equal in YJV allergy. The incidence of SE and of SRs to the CH was slightly, but not significantly, lower in male than in female patients receiving VIT with both HBV and YJV. The female preponderance in YJV-allergic patients would thus rather favor more SEs and SRs to the CH. More patients with HBV allergy were receiving a maintenance dose of 200 pg. This cannot be the reason for the lower efficacy and safety of VIT with HBV because efficacy was better and safety was similar in patients receiving the higher maintenance dose. Also, the fact that more HBV-allergic patients had an early CH cannot be the reason because the early CH caused somewhat fewer SRs than the late CH. Difference in manufacturing allergen extracts

of

HBV is obtained by electrostimulation, and YJV is obtained by venom sac extraction. The latter contains considerable amounts of body proteins ,23*24and thus, its allergenic potency may be reduced. A lower potency could explain the lower sensitivity of diagnostic tests, especially the RAST, and also the better tolerance of these extracts, but not their higher efficacy. Here, an adjuvant effect of body protein admixture might be postulated or else the reliability of the CH with the YJ might be contested (see below). Some observations, however, do not fit the hypothesis of lower allergenic potency of YJV extracts. Thus, YJV obtained by electrostimulation and by venom sac extraction have been demonstrated to be of comparable allergenic potency in RAST-inhibition assays.24Furthermore, VIT with YJV obtained by electrostimulation does not appear to induce more SEs than that obtained with the commercial venom sac extracts (Reisman RE. Personal Communication). HBV is more allergenic

tibodies is, however, not correlated to the severity of Hymenoptera sting reactions and the incidence of SE of VIT.” CH with the YJ is less reliable

The CH is often considered as the gold standard to judge the efficacy of VIT.9, lo,27-30However, it has its flaws as well. Thus, the amount of venom delivered is influenced by a number of variables, such as the duration of the sting, the starting amount of venom in the venom sac, the age of the stinging insect, the season, etc.9, ” By fixing the duration of the sting to 1 minute, we attempted to standardize the procedure as best as possible. Some observations suggest that the CH with the YJ is less reliable than that with the HB. Significantly more SRs are induced by HB than by YJ CH, not only in patients receiving VIT but also in untreated individuals with Hymenoptera sting allergy. Thus, Blaauw and Smithuis*’ reported a 50% SR rate after a CH in 38 HB-allergic patients as compared to a 23% SR rate in 50 YJ-allergic patients. Similar results were published by Kampelmacher and Van der Zwan.*’ The YJ CH could be less reliable because the amount of venom delivered with one sting, according to one study, 3’ is much smaller and subject to more variation than with an HB sting. Furthermore, YJs may squirt their venom in the air for defense without actually stinging, for example, when they are being caught for a CH. This hypothesis could explain the better results of VIT with YJV but not, of course, its superior safety. Although the relative contribution of these different aspects to the observed difference in safety and efficacy of VIT with HBV and YJV remains unclear, the following conclusions can be drawn: 1. Results obtained from studies on YJV allergy cannot be extrapolated to allergies to other Hymenoptera venoms and vice versa. 2. In all studies on Hymenoptera-venom allergy, results should be presented separately for the various Hymenoptera species. We thank Mrs. K. Freihurghaus and Mrs. M. Weber for skilled technical assistance, and Mrs. M. Schenk for expert preparation of the manuscript.

than YJV

Higher IgE-antibody responses to HBV were found in this study in confirmation of previous observations . “3 “3 25 In animal models, an adjuvant effect of melittin, the main component of HBV, on IgE production has been demonstrated.26 A peptide with comparable properties does not appear to be present in Vespulu venoms. The titer of venom-specific IgE an-

REFERENCES 1. Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61. 2. Miiller U. Thnrnheer U, Patrizzi R, Spiess J, Hoigm? R. Immunotherapy in bee sting hypersensitivity: bee venom versus whole body extract. Allergy 1979;34:369-78. 3. Reisman RE. Insect allergy. In: Middleton E Jr, Reed CE, Ellis

VOLUME89 NUMBER2

4.

5.

6. 7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

17. 18.

EF. eds. Allergy: principles and practice. 2nd ed. St. Louis: CV Mosby, 1983:1361. Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980;92:620-4. Golden DBK, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Dose dependence of Hymenoptera venom immunotherapy. J ALLERGY CLW IMMUNOL 1981;67:370-4. Mosbech H, Malling HJ, Biering I, et al. Immunotherapy with yellow jacket venom. Allergy 1986;41:95-103. Nataf P, Guinnepain MT, Herman D. Rush venom immunotherapy: a 3-day programme for Hymenoptera sting allergy. Clin Allergy 1984; 14:269-75. Gillman SA. Cummins LH, Kozak PP, Hoffman DR. Venom immunotherapy: comparison of “rush” vs “conventional” schedules. Ann Allergy 1980;45:351-4. Miiller U, Helbling A, Bischof M. Predictive value of venomspecific lgE, IgG and IgG subclass antibodies in patients on immunotherapy with honeybee venom. Allergy 1989;44: 412-8. Przybilla B. Ring J, Griesshammer B, Braun-Falco 0. Schnellhyposensibilisierung mit Hymenopterengiften. Dtsch Med Wschr 1987;112:416-24. Thumheer U, Mliller U, Stoller R, Lanner A, Hoignk R. Venom immunotherapy in Hymenoptera sting allergy. Allergy 1983;38:465-75. Ramirez DA, London0 SA, Evans R. Adverse reactions to venom immunotherapy. Ann Allergy 1981;47:435. Rocklin RE, Alfano N, Sobotka AK, Rosenwasser LJ, Findlay SR. Low incidence of systemic reactions during venom immunotherapy. J ALLERGY CLIN IMMUNOL 1982;69:125. Adolph J, Dehnert I. Fischer JF, Wenz W. Ergebnisse der Hyposensibilisiemng mit Bienen- und Wespengift. 2 Erkr Atmungsorgane 1986;166:119-24. Bousquet J, Fontez A, Aznar R, Robinet-Levy M, Michel FB. Combination of passive and active immunization in honeybee venom immunotherapy. .I ALLERGY CLIN IMMUNOL 1987;79:947-54. Yunginger JW, Paul1 BR, Jones RT, Santrach PJ. Rush venom immunotherapy program for honeybee sting sensitivity. J ALLERGY CLIN IMMUNOL 1979;63:340-7. Mliller UR. Insect sting allergy: clinical picture, diagnosis, and treatment. Stuttgart, New York: Gustav Fischer Verlag, 1990. Lantner R, Reisman RE. Clinical and immunologic features and subsequent course of patients with severe insect-sting anaphylaxis. .I ALLERGY CLIN IMMUNOL 1989;84:900-6.

Bee and

yellow

jacket

venom

differences

535

19. Schuberth KC, Graft DF, Kagey-Sobotka A, Kwiterovich KA. Szklo M, Lichtenstein LM. Do all children with insect aJler&y need venom therapy [Abstract]? J AI.I.ERGY CI.lN IMMtlNOL 1983:71:140. 20. Mueller HL. Diagnosis and treatment of in%ecl sensitivity. J Asthma Res 1966;3:331-3. 21. Lackey RF, Turkeltaub PC, Olive ES, Hubhrtrd IM. BairdWarren IA, Bukantz SC. The Hymenoptera venom study 111: safety of venom immunotherapy. J AI~I.EKCIY i’l.tu tM?vRWX. 1990;86:775-80. 22. Rzany B, Przybilla B, Jarisch R, et al. Clinical characteristics of patients with repeated systemic reactions during specific immunotherapy with Hymenoptera venoms. Allergy I99 1: 46:25 l-4. 23. Hoffman DR. Allergens in Hymenoptera venoms IV: Comparison of venom and venom sac extracts ! 41.i,tixcv CL.IN IMMUNOL 1977;59:367-70. 24. Mliller U , Reisman R, Wypych J , et al. Comparison of vespid venoms collected by electrostimulation and by venom sac extraction. J ALLERGY CLIN IMMUNOL 198 1;68:254-6 I. 25. Wiitbrich B, Wick H, Crass B, Wyss S. ZUT I9iagnostik der Hymenopterenstich-Allergie: ein Vergleich rwischen Anamnese, Hauttesten und IgE-Bestimmungen (RAST) mit Giftextrakten. Praxis 1981;70:934-43. 26. Kind LS, Ramaika C, Allaway E. Antigenic. adjuvant and permeability enhancing properties of melittin in mice. Allergy 1981;36:155-60. 27. Blaauw PJ. Smithuis LOMJ. The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venom by means of an in-hospital insect, sting J At.LERGYCLIN IMMUNOL 1985;75:556-62. 28. Kampelmacher MI, Van der Zwan JC. Provoca:ation test with a living insect as a diagnostic tool in systemic reactions to bee and wasp venom: a prospective study with emphasis on the clinical aspects. Clin Allergy 1987;17:31’7-27 29. Golden DBK, Addison BI, Gadde J, Kagey-Sobotka A. Valentine MD, Lichtenstein LM. Prospective observations on stopping prolonged venom immunotherapy. .I .?!.I ERGY CLIN IMMUNOL 1989;84: 162-7. 30. Miiller U. Berchtold E, Helbling A. Honeybee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients. 3 ALI fKGJ' CI.IN IMMUNOL 1991;87:702-9. 3 1. Hoffman DR, Jacobson RS. Allergens in Hymenoptera venom XII: how much protein is in a sting? Ann Al!ergy 198452: 276-8.