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Year : 2021  |  Volume : 35  |  Issue : 2  |  Page : 94-98

Successful treatment with a combination of bee venom immunotherapy and omalizumab for recurrent anaphylaxis after honey bee sting

1 National Allergy Centre, BLK Super Speciality Hospital, New Delhi, India
2 National Allergy Centre, New Delhi, India
3 Kashmir Institute of Allergy and Sleep Sciences, Srinagar, Jammu and Kashmir, India

Date of Submission12-Jul-2021
Date of Acceptance01-Mar-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
Dr. P C Kathuria
National Allergy Centre, BLK Super Speciality Hospital, 1/3 East Patel Nagar, New Delhi - 110 008
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijaai.ijaai_28_21

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Hymenoptera venom hypersensitivity reaction affects about 3% of the general population and a higher percentage (14%–43%) in beekeepers. Bee venom immunotherapy (bVIT) is effective in reducing subsequent severe systemic reactions and has a significant beneficial effect on disease-specific quality of life in both children and adults. In patients with a history of recurrent systemic anaphylactic reaction with bee venom, successful bVIT is difficult to achieve and can often lead to withdrawal of treatment. The combination of bVIT and omalizumab is a good option for these patients. Omalizumab is a humanized nonanaphylactogenic monoclonal anti-immunoglobulin (Ig) E antibody against the Cε3 domain of IgE to reduce the allergenicity, if combined with bVIT. We describe a successful treatment with combined omalizumab and bVIT in a case of recurrent anaphylaxis by honey bee sting hypersensitivity. Herein, subcutaneous omalizumab 150 mg was started 15 days before the initiation of bVIT and subsequently once a month for 30 months along with cluster doses of bVIT till the cumulative dose of 100 μg was achieved successfully.

Keywords: Bee venom allergy, anaphylaxis, venom, insect sting, Hymenoptera, venom immunotherapy, bee venom immunotherapy, omalizumab

How to cite this article:
Kathuria P C, Rai M, Hassan G. Successful treatment with a combination of bee venom immunotherapy and omalizumab for recurrent anaphylaxis after honey bee sting. Indian J Allergy Asthma Immunol 2021;35:94-8

How to cite this URL:
Kathuria P C, Rai M, Hassan G. Successful treatment with a combination of bee venom immunotherapy and omalizumab for recurrent anaphylaxis after honey bee sting. Indian J Allergy Asthma Immunol [serial online] 2021 [cited 2022 Dec 2];35:94-8. Available from: https://www.ijaai.in/text.asp?2021/35/2/94/350077

  Introduction Top

Insect venom hypersensitivity reaction is one of the most common causes of anaphylaxis in humans and is a medical emergency. Several meta-analyses and randomized control studies have proven that venom immunotherapy (VIT) is effective for preventing anaphylaxis to bee sting and improves the quality of life. Hymenoptera belonging to the genus bee (Apis), bumblebee (Bombus), wasp (family: Vespidae, genus: Dolichovespula, Polistes, and Vespula), hornet (Vespa) and stinging ant (family: Formicidae, genus: Myrmecia and Solenopsis), are the most studied in terms of allergy and allergen-specific immunotherapy.[1],[2] Hymenoptera-induced insect stings have an incidence of 94.5% of the general population being stung at least once in their lifetime.[3] Sensitization to Hymenoptera is 27%–40% in adults and almost 50% in children.[4] Severe anaphylactic reactions are seen in up to 3.3% of the population of the United States and 0.3%–7.5% of the European population, while in beekeepers, it is fairly high between 14% and 43%.[3],[5] The mortality rate in the general population is very low, 0.03%–0.48% per 1000,000 people.[6],[7] The risk of fatal anaphylaxis is very high in patients of mastocytosis (elevated serum tryptase reference range <11.4 μg/L), and such patients require life-long VIT.[8],[9] Other risk factors include older age, male sex, white race, vigorous exercise, cardiovascular diseases with concomitant use of beta-blocker, or ACE inhibitor.[10]

A survey of European network of severe allergic reactions found that 42.8% (>18 years) and 20.2% (in children) of severe anaphylactic reactions occur due to insect stings.[11] It is assumed that 0.4%–0.8% of children and 3% of adults show potentially life-threatening systemic reactions after an insect sting.[12],[13] Honey bee plays an outstanding role in pollination and for producing honey and bee wax. Three honey bee species – Apis mellifera (common honey bee), Apis cerana (eastern honey bee), and bumblebees (Bombus species) – are common. They are the only stinging Hymenoptera species that nearly always leave their stinger with adherent venom sac in the skin of the victim person. Bees inject 50–140 μg of venom, whereas wasps deliver nearly 3 μg of venom with each sting. Bees can sting once, but wasps have the capacity to sting multiple times.[14],[15],[16] A number of studies described bee venom as a major risk factor with a 3.1–6-fold higher risk for systemic adverse events during VIT.

The diagnosis of honey bee venom hypersensitivity reaction comprises a history of systemic hypersensitivity reaction after sting bite along with positive skin test or the detection of venom-specific IgE antibodies. The skin tests are performed as prick test or intradermal test with commercial honey bee venom and vespid venom extract at least 2 weeks after the sting hypersensitivity reaction.[17]

VIT is effective in preventing anaphylactic sting reaction, and the efficacy of wasp VIT is 95% and 75%–85% for bee venom allergic patients. Multicenter studies report that up to 20% of patients undergoing VIT have systemic reaction to immunotherapy, which results in early discontinuation of VIT.[6] Many clinical allergists in Europe use aluminum hydroxide-adsorbed venom for conventional protocols, whereas others use aqueous preparations for the buildup with accelerated protocols and then change to aluminum hydroxide-adsorbed venoms which have a comparable efficacy to aqueous venoms but are usually somewhat better tolerated for maintenance immunotherapy.[18] Cluster, rush, and ultra-rush protocols have the advantage of inducing a more rapid protection and are therefore recommended in highly exposed individuals during the Hymenoptera flying season. Moreover, the number of visits during buildup phase is greatly reduced. However, the incidence of side effects is somewhat higher in these rapid buildup protocols, especially in bee venom allergic individuals.[19]

Omalizumab, a recombinant humanized monoclonal antibody, has been used as premedication of VIT. Omalizumab acts by decreasing the Total IgE level as well as downregulates the high and low affinity receptors (FcεRI/II receptors) on mast cells.[20],[21] Omalizumab has been successfully used for the pretreatment of patients who experienced systemic reactions to VIT including patients with indolent systemic mastocytosis and adverse effects due to VIT. However, the duration of therapy and optimal dosing schedule is not clearly established. While in some cases a single injection before initiation of VIT was used, others used 3–5 injections. In other cases, omalizumab and VIT were combined for several months or even an unlimited pretreatment before maintenance dose (MD) was administered.[20] This suggests that the dose and duration of omalizumab depend on the individual susceptibility to risk factors such as patients on beta-blockers, ACE inhibitors, mastocytosis, and those treated with honey bee venom. The Omalizumab dose schedule combined with allergen immunotherapy has been researched in various studies.

We describe a patient of successful immunomodulating effect of combined VIT and omalizumab for 30 months and further followed up for 4 years without any history of anaphylaxis after honey bee sting bite anaphylaxis.

  Case Report Top

A 38-year-old male presented with a history of recurrent episodes of severe anaphylaxis (circulatory collapse and unconsciousness) few minutes after honey bee sting. Each episode of anaphylaxis was treated with emergency adrenaline injection along with supportive therapy and recovered without any sequelae. His past medical history was insignificant for any atopic diseases. The specific IgE by ImmunoCAP Assay for Yellow wasp was 0.79 kUA/L, Honey bee venom was 11 kUA/L and was negative for rest of the aeroallergens, suggestive of sensitization. Skin prick test was 5 mm for histamine, 4 mm for commercial extract of yellow wasp, and 7 mm for honey bee venom. The patient was advised bee VIT (bVIT) as per cluster protocol combined with omalizumab (anti-IgE). The patient tolerated the increasing doses very well till the MD of 100 μg was achieved. bVIT was continued for 30 months with 30 injections of omalizumab.

  Discussion Top

Immunotherapy with honey bee venom gives full protection in 80%–90% of the cases, whereas immunotherapy with Vespula venom is 95%–98% effective.[19],[22] The major problem of VIT is severe anaphylactic reaction during the buildup phase of AIT with greater risk in patients on beta-blockers, ACE inhibitors, mastocytosis, and those treated with honey bee venom. In such at-risk individuals, specific bVIT has to stop due to severe anaphylaxis, grade IV (hypotension, dyspnea, and angioedema). The diagnosis of honey bee venom allergy comprises the patient history of a systemic sting reaction, a positive skin test response, and/or the detection of venom-specific IgE antibodies.[9] In our case, skin test (7 mm) and specific IgE (11 kUA/L) [Table 1] were immunologically positive.
Table 1: Clinical characteristics with skin prick test, specific immunoglobulin E, and PFT

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The starting dose of VIT is between 0.001 and 0.1 μg injected subcutaneously. The recommended MD is 100 μg of venom protein, corresponding to one to two bee stings and probably many more Vespula stings.[23]

It is well known among clinical allergists that there could be severe adverse reaction during buildup phase of bVIT. Premedication with omalizumab can improve the efficacy of VIT. Omalizumab binds free IgE and hence prevents IgE binding to FcεRI on mast cells, basophils, and eosinophils, consequently leading to the downregulation of IgE receptors and total IgE.[24],[25] There are no clear-cut guidelines, combining omalizumab with VIT on optimal dosing and duration of omalizumab. As per various studies, the dose of omalizumab combined with AIT in specific indications, is variable [Table 2].
Table 2: Schedule and duration of combined venom subcutaneous cluster immunotherapy venom immunotherapy (0.5 ml=100 μg) along with injection omalizumab therapy 150 mg per month

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In our case, the concomitant administration of VIT and omalizumab induced better tolerance. Injection omalizumab was given 15 days before initiation of bVIT. We could start cluster doses (4 allergen shots of increasing doses, 0.01mL, 0.02mL, 0.03mL, 0.04mL) at 60 minutes intervals to achieve the cumulative dose of 20 ug. in subsequent 4 visits, with increasing cluster doses every 10-15 days [Table 2] over the next 8-9 weeks to achieve MD of 100 ug, under premedication of fexofenadine, methylprednisolone 16 mg, and montelukast 10 mg, 2 h before initiation of bVIT. As soon as MD was achieved, the treatment interval was increased to monthly injection of 0.5 ml (100 μg) for 30 months. The patient was followed up for 4 years with no history of recurrence of bee sting-related anaphylaxis. Various clinical trials on the dose and duration of omalizumab in allergic disorders (food allergy, respiratory allergy, insect hypersensitivity have been performed [Table 3].
Table 3: Omalizumab dose schedule combined with allergen immunotherapy

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A case of successful desensitization with honey bee venom has been reported.[26] Few other case reports have reported success in desensitization of anaphylaxis due to cannabis and horse dander.[27],[28] The author has also reported the efficacy of combination therapy of omalizumab and house dust mite allergen immunotherapy in severe refractory steroid-dependent atopic dermatitis with rhinitis and asthma.[29]

  Conclusion Top

The combination therapy of bVIT and omalizumab has a powerful, protective, and immunomodulatory effect, which not only alleviates risk during the buildup phase, decreases the duration of bVIT, but also has long-lasting effects. We hypothesize that a successful bVIT can be achieved in high-risk patients experiencing recurrent anaphylaxis by combining it with omalizumab. Further studies are required to confirm the efficacy, safety, and long-term effect of bVIT in high-risk patients of recurrent anaphylaxis due to bee sting hypersensitivity reaction.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Full text]  
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  [Table 1], [Table 2], [Table 3]


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