Q:

7/24/2013
42 year-old patient, former amateur bee keeper presented with repeated rapid-onset collapse after bee sting 3 times. Skin test positive for bee, negative for other hymenoptera. Baseline tryptase elevated 28. Got ultrarush desensitization under premedication with cetirizine and montelukast, reacted at the 20 mcg dose (flushing, malaise) but responded to IV diphenhydramine and dose was repeated and protocol completed up to a dose of 120 mcg in the same day without any problem. Came back to clinic 1 week after for the first maintenance (under cetirizine premed) shot that I decided to split. Got 50 mcg and had anaphylactic shock 15 minutes after with flushing, tachycardia (150) and hypotension (140/90 to 90/30) needed 2 doses of IM Epi and IV volume. What should I do next...slow progression protocol? (Of what kind?) Xolair for a few months and then repeat ultrarush protocol. He is at great risk of being restung and likely has indolent mastocytosis (c-kit mutation pending). Thank you!

A:

Thank you for your inquiry.

I am going to comment briefly about one of your questions, but I am going to ask Dr. Beatrice Bilo, who has published extensively on venom immunotherapy to honeybee, with an emphasis on the care of beekeepers, to reply specifically to your questions regarding honeybee venom immunotherapy. When we receive Dr. Bilo’s response, we will forward it to you.

In the meantime, however, Dr. Bilo has responded previously to an “Ask the Expert” inquiry regarding the dose of honeybee venom required for protection. I have copied the pertinent paragraph below regarding bee venom dosing. In addition, she has written an excellent article specifically related to bee venom immunotherapy, and this reference and its abstract is also copied below.

While we are awaiting her response to your inquiry, I will make a comment regarding your potential diagnosis of indolent systemic mastocytosis. I agree that the patient most likely does have indolent systemic mastocytosis. You did not state whether you performed a bone marrow; just saying that you are awaiting the results of an analysis of c-KIT mutations. I would not, however, rely on this mutation in the blood. In my opinion, you would need a bone marrow to analyze the mutation and interpret it in light of the accompanying histology/pathology.

The second comment regards the use of omalizumab in this situation. I do think it would be helpful based on the results of previous investigations, and would suggest you consider it. There of course may be barriers to this posed by insurance coverage.

Having made these comments, I again mention that I will forward you Dr. Bilo’s response as soon as we receive it.

Thank you again for your inquiry.

Response from Dr. Beatrice Bilo to a Previous Ask the Expert Inquiry:
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?).

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.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Bilo regarding your Ask the Expert inquiry. 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:
First, the patient needs to be treated with immunotherapy ASAP but at the same time, on my opinion, he has to stop beekeeping.

I agree with Dr. Lieberman that it is important to confirm and define the presence of a mastcell disorder, even if an elevated baseline serum tryptase level itself represents an important risk factor for severe anaphylacticreactions and does indicate the need to perform VIT (Rueff JACI 2009).

What schedule, extract and premedication could be used in this patient? The answer is not easy.

1. Schedule. According to some studies (Rueff JACI), ultrarush seems to induce more side effects than slower protocols, even thought no comparative data exist in patients with mastcell disorders. Thus, based on these data, I have to suggest a conventional protocol. However, in my personal experience, even in mastocytosis patients, the rush protocol for bee venom and the ultra-rush protocol I am used since 20 years now are as safe as the conventional one. Please find enclosed my paper in which you can find my rush protocol for bee venom allergic patients, in the case Dr. Drolet wants to use it.

2. Type of extract. In some European countries, like Italy, but probably not yet in USA, non purified aqueous as well as purified aqueous extracts (PA) (Aquagen Alk) and purified aluminium hydroxide adsorbed (PAHA) (depot preparation:Alutard - Alk) preparations are commercially available. The PA extracts can be used for ultrarush, rush, clustered and maintenance phases, while PAHA preparations are only administered for the conventional build-up and maintenance schedule. Many European special¬ists (including myself) switch to depot preparations following the up-dosing phase. In 2011 (see below) I published a paper showing that systemic reactions during the build-up phase using a 5-day rush protocol occurred significantly more often in patients treated with nonpurified aqueous extract than in those treated with the corresponding purified aqueous preparations. This was demontrated for patients with normal baseline tryptase level. In my experience (data not published) the same seems to occur in mastocytosis patients.

3. Premedication. Omalizumab could be a solution, if Dr. Drolet is able to obtain it. In Italy at the moment it is almost impossible to have Omalizumab for venom allergic patients. So I have no direct experience in handling Omalizumab as premedication for VIT. What can we learn from the literature is that pre-treatment with anti-IgE monoclonal antibodies has been successful used in several case reports of bee venom allergic patients, including patients with indolent systemic mastocytosis. And almost all (but not all) of whom experienced systemic reactions to VIT were able to tolerate VIT after pre-treatment with Omalizumab. However, until now the optimal time for its administration during VIT, the appropriate dosage, the long term effects, and the best incremental protocol of VIT to be used still remain unknown. I suggest to follow the indication of Kontou-Fili, a Greek Allergist of whom I personally know her experience and professionalism seriousness.

Honeybee VenomImmunotherapy: A Comparative Study Using Purified and NonPurified Aqueous Extracts in Patients with Normal Basal SerumTryptase Concentrations

High omalizumab dose controls recurrent reactions to venom immunotherapy in indolent systemic mastocytosis

Prolonged high-dose omalizumab is required to control reactions to venom immunotherapy in mastocytosis

With best regards,
M.Beatrice Bilò, MD

AAAAI - American Academy of Allergy Asthma & Immunology