Q:

4/3/2013
I have a pt with IgE positive Honeybee anaphylaxis (tryptase nl) that wants to know when she can return to her bees. I tried to dissuade her from this. She has reached 1.0 ml maintenance beginning of March. I have no experience with "challenges" like this - should I measure her HB IgG level first? Thank you.

A:

Thank you for your inquiry.

First of all, I would like to offer you some reassurance that immunotherapy appears to be an effective therapy in beekeepers and the vast majority do well (see Munstedt, et al., abstract copied below). However, as you note, managing beekeepers with hypersensitivity to bees can be “a challenge.” There is an excellent article by Bilò, Antonicelli, and Bonifazi (see abstract copied below) that deals with these issues in detail and offers very pertinent clinical suggestions in this regard.

I am going to ask the first author of this article, Dr. Bilo, to share her thoughts with us regarding your inquiry. When I hear from her, I will forward her response to you.

One of the things that I would ask her to answer is whether or not the measurement of an IgG anti-bee venom would be helpful to you in this instance. As you can see from the additional abstracts copied below, there is some controversy as to the usefulness of measuring IgG anti-bee venom in this situation. Some studies have found it to be useful and others have not.

Again, when I hear from Dr. Bilo, I will send her response to you. In the meantime, I believe you will find her article in the Journal of Immunotherapy extremely helpful.

Thank you again for your inquiry.

J Investig Allergol Clin Immunol. 2010;20(1):58-62.
Efficacy of venom immunotherapy in beekeepers.
Münstedt K, Wrobel D, Kalder M.
Source
Department of Obstetrics and Gynecology, University Hospital Giessen and Marburg, Justus Liebig University, Giessen, Germany.
Abstract
Introduction: We previously found that some beekeepers continue beekeeping even after experiencing systemic allergic reactions. The present study was performed to collect data on the experience of beekeepers who underwent desensitization and continued beekeeping. The results are important for future counseling in this group of patients, and they show the effectiveness of desensitization under real conditions.
Methods: With the help of German and American beekeeping journals, we asked beekeepers who had undergone desensitization to participate. Data were obtained using a newly developed questionnaire and supplemented by reports obtained from the physicians who treated the allergy.
Results: We sent a questionnaire to each of the 73 beekeepers who responded to our call, and 63 (86.3%) questionnaires were returned. The vast majority of participants were hobby beekeepers who developed signs of allergy after a median of 2 years' beekeeping (mean, 4.27 years) and a median of 15 stings (mean, 51 stings). Additional allergies were reported by 35 beekeepers. Forty-three beekeepers were evaluated to determine the effectiveness of desensitization. The average number of bee stings after desensitization was 107 (median 18). All but one reported no longer having allergic responses; however, in the case of those that did, the severity of the allergic symptoms improved significantly.
Conclusion: To our knowledge, this study is the first to provide data on the experience of beekeepers who continue their activity after desensitization. Our results show that desensitization can result in a complete absence of symptoms after re-exposure to bee stings.

Immunotherapy. 2012 Nov;4(11):1153-66. doi: 10.2217/imt.12.113.
Honeybee venom immunotherapy: certainties and pitfalls.
Bilò MB, Antonicelli L, Bonifazi F.
Source
Allergy Unit, Department of Immunology, Allergy & Respiratory Diseases, University Hospital Ospedali Riuniti di Ancona, Ancona, Italy.
Abstract
The honeybee is an interesting insect because of the fundamental agricultural role it plays, together with the composition of its venom, which presents new diagnostic and immunotherapeutic challenges. This article examines various aspects of honeybee venom allergy from epidemiology to diagnosis and treatment, with special emphasis on venom immunotherapy (VIT). Honeybee venom allergy represents a risk factor for severe systemic reaction in challenged allergic patients, for the diminished effectiveness of VIT, for more frequent side effects during VIT and relapse after cessation of treatment. Some strategies are available for reducing the risk of honeybee VIT-induced side effects; however, there is considerable room for further improvement in these all-important areas. At the same time, sensitized and allergic beekeepers represent unique populations for epidemiological, venom allergy immunopathogenesis and VIT mechanism studies.

Clin Exp Allergy. 1993 Aug;23(8):647-60.
Venom-specific IgG antibodies in bee and wasp allergy: lack of correlation with protection from stings.
Ewan PW, Deighton J, Wilson AB, Lachmann PJ.
Source
Molecular Immunopathology Unit, MRC Centre, Cambridge, U.K.
Abstract
This paper investigates the relationship between venom IgG levels and protection from stings. Venom-specific IgG antibody levels have been measured by radioimmunoassay in untreated wasp-(n = 38) and bee-allergic (n = 16) patients presenting with systemic reactions to stings and in a sub-group of these (wasp = 15; bee = 9), before and after the initial course of venom immunotherapy (VIT). A history was taken of all reactions, the last systemic reaction being graded on a scale of 1-8 and of the number and timing of stings. In untreated patients venom IgG levels were much higher in bee-allergic patients (mean +/- s.e. = 68.2 +/- 7.1% positive pool) than in the wasp group (27.1 +/- 4.2%) (P < 0.05 Mann-Whitney U-test). There was a marked rise in venom IgG after the initial course of VIT in the wasp group (geometric mean and 95% confidence intervals = 40.5%, 28.8-54.3) but a much smaller rise in the bee group (15.3%, 6.6-24.1), with no overlap in the 95% confidence intervals. Bee patients, who were mainly beekeepers or their relatives, had been more heavily immunized with venom than wasp patients. They had received: (i) more stings (mean number of stings: bee, 26; wasp, 4; P < 0.001) and (ii) more stings per year. Wasp patients received their smaller number of stings over a much longer period, up to 40 yr. There was no correlation between the severity of the last systemic reaction and the venom IgG levels alone or venom IgG and IgE levels in combined analysis in either bee or wasp patients. This study shows that the pattern of IgG response differs in bee and wasp-allergic subjects, and that most bee-allergic subjects with systemic reactions have high levels of venom IgG. The degree of immunization with venom seems to be an important determinant of the venom IgG level. Our findings suggest that venom-specific IgG levels do not predict systemic reactions to stings and are not useful for monitoring VIT. If protection from stings is IgG-mediated, our observations suggest that the relevant immune response is more complex, possibly involving IgG sub-classes, IgG antibodies to individual venom antigens or antibody affinity, and not adequately reflected by measurement of the concentration of venom-specific IgG.

Clin Allergy. 1983 May;13(3):229-34.
Venom-specific IgE and IgG antibodies as a measure of the degree of protection in insect-sting-sensitive patients.
Urbanek R, Krauss U, Ziupa J, Smedegård G.
Abstract
Venom-specific IgE and IgG antibodies were measured in the sera of bee-venom-sensitive patients during a 3-year hyposensitization period. The level of specific IgG antibodies initially increased, and 2 months after the start of therapy, this increase was on average five-fold. A concomitant but non-significant increase in specific IgE antibodies was also observed initially. Later during the treatment period specific IgE antibodies showed a continuous decline and after 3 years the level was one third of the pre-treatment level. Venom-specific IgG antibodies, however, remained above the pre-treatment level. The disappearance of the severe allergic reactions was related to the level of both IgE and IgG antibodies as demonstrated in seventy-six bee sting challenges. In patients with specific IgG antibody levels above 400 u/ml, no severe reactions were observed even if the patient had levels of specific IgE antibodies of RAST class 3 or 4. These data suggest that the relationship between venom-specific IgE and IgG antibodies permits an evaluation of the state of immunity to insect stings.

Clinical correlation of the venom-specific IgG antibody level during maintenance venom immunotherapy
Golden et al.
Journal of Allergy and Clinical Immunology
Volume 90, Issue 3, Part 1, September 1992, Pages 386–393
Allergen immunotherapy is associated with a significant increase of specific IgG antibodies that have been suggested as a mechanism of action and as a marker of efficacy for immunotherapy. The value of venom-specific IgG antibody determinations as a measure of clinical protection against sting anaphylaxis has been difficult to prove in individual patients. We performed 211 insect sting challenges in 109 patients over a 4-year period to determine the significance of venom IgG levels 3 μg/ml or lower. Systemic symptoms occurred in only 1.6% of those with venom IgG more than 3 μg/ml, but in 16% of those with less than 3 μg/ml IgG, and notably in 26% of patients with low venom IgG who had received less than 4 years of treatment. The venom IgG level had no predictive value in patients who had received more than 4 years of therapy. Honeybee sting data were inconclusive because of the small number of subjects. We conclude that low venom-specific IgG levels are associated with an elevated risk of treatment failure during the first 4 years of immunotherapy with yellow jacket or mixed vespid venoms.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Beatrice Bilo. Thank you again for your inquiry and we hope this response is helpful to you.
 
Sincerely,
Phil Lieberman, M.D.
 
Response from Dr. Beatrice Bilo:
1. Honeybee VIT is less effective than Vespid VIT. The recommended maintenance dose of 100mg of venom prevents SRs in approximately 75-85% of HB allergic patients. Moreover, since BKs may receive multiple stings at a time, even with protective clothing, a dose of 200 µg or more is recommended. Some European experts suggest performing a sting challenge in order to verify VIT protection with 100 µg before going back to beekeeping; otherwise, an increased dosage of HB venom is administrated. The situation could be probably different if the beekeeper developed an anaphylactic shock to multiple stings. (Did Dr. Purser's patient develop an anaphylactic shock after one single sting or multiple stings? Did she tolerate VIT without any side effect?)

2. As for the usefulness of measuring IgG anti-bee venom, there is no close correlation between the IgG titer and the clinical efficacy of VIT, while one does exist between IgG4 concentrations and the number of annual stings and years spent in beekeeping.

3. In few studies a basophil activation test showed a higher reactivity in patients who still reacted to bee or wasp compared with those who tolerated field stings. However, studies including larger number of patients in whom a sting challenge test is performed are required to confirm these promising results.

In conclusion, if the patient developed an anaphylactic shock after one single bee sting, I suggest increasing the maintenance dose up to 200 µg before reassuring her that she can return to her bees.

I do not use the level of HB sIgG as a parameter of the clinical efficacy of VIT.

With best regards,
M.Beatrice Bilò, MD
EAACI Interest Groups Representative
Incoming President of AAITO (Italian Association of Hospital and Territorial Allergists and Immunologists) Allergy Unit - Department of Allergy, Immunology and Respiratory Diseases - University Hospital Ospedali Riuniti di Ancona- Italy Via Conca 71 - 60020 Ancona (Italy)

AAAAI - American Academy of Allergy Asthma & Immunology