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Keywords:

  • anaphylaxis;
  • bumblebee venom;
  • efficacy;
  • Hymenoptera;
  • immunotherapy;
  • safety

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Background: The objective was to investigate whether venom immunotherapy with bumblebee venom (BBV) is safe and effective.

Methods: Eleven patients with severe occupational anaphylaxis caused by stings of bumblebees were studied. Sensitization to bumblebee venom was confirmed by skin tests and RAST. Immunotherapy was started with bumblebee venom extract by the semirush procedure, because these patients showed a primary sensitization to Bombus venom, and a low or absent degree of cross-reactivity with honeybee venom. IgE titer and skin tests with bumblebee venom were performed yearly. Efficacy was evaluated by means of in-hospital sting challenge and/or occupational field stings from bumblebees.

Results: All patients reached maintenance dose in 6 weeks without severe side-effects. During the follow-up period (1.5–5 years), three systemic reactions in two patients were seen in 20 bumblebee stings. However, these reactions were milder than the index sting.

Conclusions: Immunotherapy with bumblebee venom is safe and effective, and is comparable with honeybee and yellow-jacket venom immunotherapy.

In contrast to honeybee venom (HBV) or yellow-jacket venom (YJV) allergy, immediate-type allergy to bumblebee (Bombus terrestis) venom is rare. However, the growing use of bumblebees for the pollination of vegetable flowers in The Netherlands accounts for the increasing number of anaphylactic reactions to their stings.

The efficacy of venom immunotherapy (VIT) for the treatment of patients with allergic systemic reactions to Hymenoptera stings has been established ( 1). It was our objective to investigate whether VIT with bumblebee venom (BBV) could be safe and effective as well.

Using a semirush protocol, we started immunotherapy with purified BBV extract in patients with anaphylactic reactions to BBV.

This paper describes the results of the follow-up study, regarding side-effects, skin tests, and RAST, in hospital sting challenge and field stings, on these 11 patients with BBV immunotherapy after reaching 1.5–5 years of the maintenance dose.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Patients

We describe 11 patients with severe occupational anaphylaxis, caused by stings of bumblebees ( Table 1). Apart from a large local reaction in some patients, only patient Bo experienced an anaphylactic reaction to a previous bumblebee sting (grade IV, in the Mueller classification [ 2]).

Table 1.  Characteristics of 11 patients with bumblebee venom allergy
PatientSexAge (years)JobAnaphylaxis gradePrevious stings by bumblebees
KoM48Tomato growerIV 7
RijM48Tomato growerIV25
MuF49Garden workerIV 1
MiM47Tomato workerII 3
WuF44Tomato growerIII15
BoM49Tomato growerIV15
KeM35Bumblebee farm workerIII 4
KjrM25Tomato growerIV 2
BuM35Bumblebee farm workerIII15
ViM47Tomato growerIV 2
ScM31Tomato growerII, III 5

Immunotherapy

As earlier described by de Groot et al. ( 3), patients Ko and Rij showed no evidence of cross-reactivity between BBV and HBV by SPT and RAST. Therefore, immunotherapy was started very cautiously in these two patients with very low doses of purified BBV extract. The maintenance dose was reached after 8 weeks without side-effects ( 3). The other patients reached the maintenance dose in approximately 5 weeks with a modified semirush protocol: week 1 – 0.001/0.01/0.1 μg; week 2 – 1/5/10 μg; week 3 – 20/30 μg; week 4 – 50/50 μg; weeks 5 and 6 and every 4 weeks thereafter – 100 μg of BBV.

Follow-up

Follow-up was performed yearly: skin test, RAST with BBV; registration of reactions caused by occasional field stings; and side-effects of the immunotherapy. This registration included severity, anaphylactic grade of the reaction, and rescue medication used. Hospital sting challenge in the first two patients was performed as previously described ( 3).

Allergens

BBV (B. terrestis) extract for skin tests (1 μg/ml) and venom for immunotherapy (100 μg/ml) were obtained from ALK Benelux, Groningen, The Netherlands. This venom was obtained by electric stimulation.

Skin test

Skin tests were performed intracutaneously with 0.02 ml of 10-fold dilutions of BBV. After 20 min, wheal-and-flare reactions were measured with the grading system of standardized plus signs devised by Norman ( 4). The lowest concentration resulting in a wheal diameter of 5 mm was qualified as positive in end-point titration. The negative control wheal with dilution buffer was considered valid only if the wheal disappeared or was less than 2 mm. The positive control test was histamine diphosphate (0.1 mg/ml).

RAST (radioallergosorbent test)

Agarose beads as allergen support were used in RAST to determine allergen specific IgE. A volume of 300 μl of BBV (ALK, Denmark), 100 μg/ml, was coupled to 300 mg of CNBr-activated Sepharose 4B (Pharmacia, Uppsala, Sweden), according to the manufacturer’s instructions.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Side-effects

During the induction phase (194 injections), we registered 12 (6.2%) local reactions (5–10 cm), and two (1%) systemic reactions, consisting of shortness of breath appearing 15 min after the injection. The asthmatic reactions resolved after the administration of B-sympathicomimetica and an antihistamine tablet. These reactions occurred in patient Kjr, who had unstable asthma caused by allergy to house-dust mite. After stabilization of the bronchial hyperreactivity with inhalant corticosteriods, no additional problems were seen.

During the maintenance regimen (393 injections), we registered 11 (2.8%) local reactions and no systemic reactions.

Sensitization

All patients showed a 10–100-fold decrease in skin test reactivity after 1 year of immunotherapy. During the next 3–4 years of immunotherapy, a continuing but slight reduction was seen. These data were confirmed by RAST, as shown in Fig. 1. Both skin test and RAST data are comparable with the IgE response during immunotherapy with HBV and YJV ( 1).

image

Figure 1. RAST with bumblebee venom.

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Efficacy

We started immunotherapy with patients Ko and Rij in 1993. After 1 year, we performed an in-hospital sting challenge, which caused in both only a local reaction. The following nine patients who started immunotherapy with purified BBV experienced 18 field stings ( Table 2). Most reactions were only local reactions; however, in two patients, three anaphylactic reactions occurred, but they were milder than for the index field sting. Two patients were anxious when stung and used Epipen® after approximately 20 min, although they did not show any signs of anaphylaxis.

Table 2.  Outcome of sting reactions during immunotherapy with purified BBV
PatientMonths after starting ITStingOutcomeTherapy
  1. HC: in-hospital challenge; FS: field sting; LR: local reaction; SR: systemic reaction (grade according to Mueller [2]).

Ko 12HCLR
Rij 12HCLR
  40FS
  48FS
  60FSLR
Mu 12FSEpinephrine
  39FS
Mi  1FSSR (I)Clemastine
Wu 36FSLREpinephrine
Bo  9FSLR
  26FSLR
Ke  8FSLR
  15FSSR (II)
  30FSSR (I/II)
Kjr 
Bu<124xFS
Vi 
SC 102xFSLR

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Immunotherapy with insect venom is already known to be safe and effective ( 1, 5). In The Netherlands, we see an increasing number of patients with allergy to BBV as an occupational disease. As bumblebees and honeybees both belong to the Apidae family, strong cross-reactivity was supposed to exist, as has been proven by Hoffman & Jacobsen ( 6) and Jacobsen & Hoffman ( 7). As BBV was then not yet commercially available for diagnostic and therapeutic purposes, Kochuyt et al. ( 8) performed immunotherapy with HBV successfully in patients with BBV allergy. Nevertheless, earlier RAST-inhibition experiments showed in our patient group a low level of cross-reactivity, an observation which can be explained by the fact that these patients were primarily stung by and sensitized to bumblebees ( 9). This explains the results of Stern et al. ( 10). They reported two patients with occupational allergy to BBV who were hyposensitized with purified HBV. Both patients developed a severe anaphylactic reaction after an incidental sting. This suggests that immunotherapy with HBV is not effective in these BBV patients. Therefore, immunotherapy with purified BBV was started in our patient group, as the degree of systemic reaction and the risk of re-exposure were high. We did not have any data on the spontaneous prognosis of patients with BBV anaphylaxis; therefore, patients were advised to change their profession or start immunotherapy.

The side-effects of BBV immunotherapy can be compared to those of bee and wasp venom immunotherapy. There was no unacceptably high incidence of side-effects. Large local reactions were seen in 6.2% during the induction phase and 2.8% during the maintenance phase. During the induction phase, two systemic reactions occurred in a patient with unstable asthma. It must be stressed that more side-effects always occur with faster schedules ( 11). Therefore, we used a semirush procedure to lower the risk of reactions.

As far as efficacy is concerned, we had 18 field stings and two hospital challenges to evaluate. A provocation test with a sting from the responsible insect is without doubt the most reliable control of the effectiveness of immunotherapy, but, as some authors have mentioned ( 12), the low grade of a sting reaction does not ensure that the patient will remain free of a systemic reaction on any next sting. Nevertheless, we emphasize that our patients are still working among bumblebees and have tolerated several field stings without complications. As misidentification by the patient at work of the stinging insect is nearly impossible, more provocation tests seemed not to be necessary. The only three systemic reactions, which occurred in two patients, were less serious than the anaphylaxis before immunotherapy. In one patient, the systemic reaction took place before the maximum dose was reached. This confirms that the effectiveness of BBV immunotherapy (85%) is comparable with that of other VIT. Earlier studies in which patients on maintenance VIT were exposed to a provocation test showed that more than 90% of YJV-allergic and 75–80% of HBV-allergic patients were fully protected ( 5, 13).

In summary, we conclude that immunotherapy with BBV is safe and effective for patients with occupational BBV anaphylaxis.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References
  • 1
    Müller UR. Insect sting allergy: clinical picture, diagnosis and treatment. Stuttgart: G. Fischer Verlag, 1990
  • 2
    Mueller HL. Diagnosis and treatment of insect sensitivity. J Asthma Res 1966;3:331 333
  • 3
    De Groot H, De Graaf-in 't Veld C, Gerth van Wijk R. Allergy to bumblebee venom. I. Occupational anaphylaxis to bumblebee venom: diagnosis and treatment. Allergy 1995;50:581 584
  • 4
    Norman PS. Skin testing In: RoseNR, FriedmanH, editors. Manual of clinical immunology. 2nd ed. Washington, DC: American Society for Microbiology, 1980:189 193
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    Müller U & Mosbech H. Position paper: Immunotherapy with Hymenoptera venoms. Allergy 1993;48 Suppl 14:37 46
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    Hoffman DR & Jacobsen RS. Allergens in Hymenoptera venom. XXVII. Bumblebee venom allergy and allergens. J Allergy Clin Immunol 1996;97:812 821
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    Jacobson RS & Hoffman DR. Characterization of bumblebee venom allergens. Allergy 1992;91:185
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    Stern A, Müllner G, Wüthrich B. Diagnosis and treatment of occupational allergy to bumblebees. Allergy 1998;53 Suppl 43:27
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    Birnhaum J, Charpin D, Vervloet D. Rapid Hymenoptera venom immunotherapy: comparative safety of three protocols. Clin Exp Allergy 1993;23:226 230
  • 12
    Franken HH, Dubois AEJ, Minkema HJ, Vd Heide S, De Monchy JGR. Lack of reproducibility of a single negative sting challenge in the assessment of anaphylactic risk in patients with suspected yellow jacket hypersensitivity. J Allergy Clin Immunol 1994;93:431 436
  • 13
    Mosbech H. Hymenoptera immunotherapy. Allergy 1997;52:1 3