Omalizumab: A useful tool for inducing tolerance to bee venom immunotherapy

Insect venom anaphylaxis occurs in about 3% of adults and venom immunotherapy (VIT) is an established treatment of sting anaphylaxis.¹ The protective effect of VIT is quite convincing, as it is associated with a success rate of 98% with wasp VIT and 75–85% with bee venom immunotherapy (BVIT). Adverse reactions may occur, especially with BVIT,² and systemic adverse reactions to BVIT are reported to occur in about 14% of patients.³

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved in Europe as add-on therapy for allergic severe asthma not controlled by standard therapy and as add-on therapy for chronic spontaneous urticaria.

Pre-treatment with omalizumab has demonstrated a role in preventing severe allergic anaphylaxis following VIT administration, as shown in several published case reports.^4-7 This efficacy is likely to be explained with the established omalizumab mechanism of action of binding free IgE and subsequent downregulation of FcϵRI on mastcells, basophils, and eosinophils.⁸ The efficacy of omalizumab pre-treatment in a case where the presence of venom specific IgE was not detected has also been reported,⁹ suggesting an additional mechanism of action, such as mast cell apoptosis due to lack of IgE binding.⁵

We describe the case of two cousins at high risk of bee stings, where treatment with omalizumab allowed a successful BVIT.

Two boys, aged 12 years (case 1) and 17 years (case 2), who were both sons of beekeepers, experienced a severe systemic reaction following a bee sting on separate occasions. Case 1 had developed systemic urticaria and angioedema with cough and dyspnea and was positive to bee skin prick tests at 100 mcg using purified venom extracts (ALK-Abellò, Milan, Italy), while the allergen-specific IgE against bee venom (BV), measured using the Pharmacia-Cap System, showed 15.4 kU/L (class III). Case 2, after a bee sting, first presented a systemic rash followed by loss of consciousness a few minutes later; BV intradermal skin test was positive at 0.1 mcg/mL and specific bee IgE levels were 12.3 kU/L (class III). Tryptase levels were not investigated as this laboratory test is not available on our premises. Both boys also had a positive history for allergic rhinitis and asthma due to dust mite sensitization defined by a positive skin prick test with concordant positive specific IgE and were under treatment with oral antihistamine (cetirizine 10 mg daily) and antileukotriene (montelukast 10 mg daily) tablets and inhaled corticosteroids (fluticasone propionate 500 mcg) in combination with a long-acting β2-agonist (salmeterol xinofoate 50 mcg) twice daily. Physical examination, chest X-ray, and ECG were without abnormalities; spirometry and laboratory tests were within normal ranges.

As the two boys were at high risk of bee stings, living in a village on the slopes of volcano Etna with a high concentration of beehives and therefore bees in the surroundings, BVIT was started following an ultra-rush schedule (Table 1) using standardized venom preparations (ALK-Abellò, Milan, Italy). Ultra-rush BVIT had to be stopped after a cumulative dose of 25 mcg of BVIT (delivered in four s.c. doses of 1, 3, 6, and 15 mcg, respectively, administered at 30 min intervals) due to anaphylaxis characterized by the occurrence of facial angioedema, hypotension (blood pressure was 70/50 mmHg in case 1 and 60/40 mmHg in case 2) and severe asthma symptoms (SO₂ 92% in case 1 and 87% in case 2). After emergency treatment with 500 mg hydrocortisone i.v. and 10 mg clorfeniramine i.m., spirometric respiratory parameters showed the drop of FEV1 levels below 80% (FEV1 74% in case 1 and 76% in case 2). The patients recovered only after adrenaline administration (0.5 mL i.m.).

Table 1.

Ultra-rush immunotherapy schedule with bee venom extract.

Allergen concentration (mcg/mL)	100	100	100	100	100	100	100
Volume of injection (mL)	0.01	0.03	0.06	0.15	0.25	0.25	0.25
Time of injection (min)	0	30	60	90	120	180	240

Bee venom extract was tolerated by both patients. The ultra-rush schedule consisted of seven consecutive doses of 0.01, 0.03, 0.06, 0.15, 0.25, 0.25, and 0.25 mcg, respectively, administered at 30 min intervals.

As both patients were treated with inhaled corticosteroids (>500 mcg/day of equivalent of beclomethasone dipropionate) in combination with long-acting β2-agonist and montelukast and still had experienced a FEV1 drop, omalizumab treatment was proposed. The level of asthma control was also evaluated by the Asthma Control Test (ACT),¹⁰ revealing a score of 18 (case 1) and 15 (case 2), pertinent to a largely uncontrolled disease.

According to the dosing schedule resulting from matching between body weight and total IgE, case 1 received 525 mg s.c. omalizumab (total IgE levels, 1500 IU/mL; body weight, 39 kg), while case 2 received 450 mg (total IgE levels, 787 IU/mL; body weight, 65 kg), both every two weeks.

Two months after starting omalizumab treatment, bee ultra-rush VIT was re-administered and a cumulative dose of 100 mcg was tolerated (Table 1) with the occurrence of only facial edema in the build-up phase, which resolved spontaneously in both patients.

Maintenance doses were administered first after 15 days and monthly thereafter with a cumulative dose of 100 mcg of BVIT with no more adverse events occurring.

The ACT score also improved during the combined treatment of BVIT and omalizumab (case 1, 25; case 2, 22) and asthma maintenance pharmacologic treatment could be decreased to 250 mcg fluticasone propionate in combination with 50 mcg salmeterol xinofoate.

After six months of omalizumab treatment, as BVIT was now well tolerated and respiratory parameters where within normal range (FEV1 104% in case 1 and 112% in case 2), omalizumab treatment was stopped while BVIT continues to be tolerated at a monthly dose of 100 mcg. Furthermore, both patients have been stung by bees several times, with only a local reaction at the injection site.

VIT is an effective method for the treatment of Hymenoptera venom allergy.¹¹

Nevertheless, it is well-known among clinicians who perform VIT that BVIT is more likely to cause adverse reactions.² Omalizumab, an anti-IgE monoclonal antibody, was reported to be effective in reducing systemic side effects and amplifying the therapeutic effect of subcutaneous immunotherapy for inhaled allergen in pollen-induced allergic rhinitis, mild–moderate allergic asthma, and venom allergy.^12-14 Omalizumab also showed to be effective for pre-treatment and concurrent treatment of BVIT when anaphylaxis had occurred during initial BVIT.^7,15

The above reported cases confirm these data and show that when omalizumab is administered to improve tolerance to initial BVIT, it can be safely stopped within six months. The duration of therapy with omalizumab in this clinical setting is not clearly established and the review of published cases shows a wide variety of approaches, suggesting that the discriminator for clinical choices is mainly the individual response to BVIT administration and the omalizumab ability to induce a better tolerance. Galera⁶ reported, out of seven cases, a duration of omalizumab therapy in the range of 5–12 months. An unlimited pre-treatment with omalizumab before every maintenance dose of VIT administered monthly has been described by Palgan⁴ while da Silva⁵ reported a concomitant administration of omalizumab and VIT for six months; after that, immunotherapy alone was tolerated for a further 13 months. In another case, the administration of omalizumab for severe asthma resulted in unexpected protection from a severe reaction after an insect sting, experienced by the same patient before omalizumab therapy initiation.⁶ The dosing schedule in published cases appears to be obtained from the approved table, as we did for both our patients; although the adherence to the dosing table is not always declared in previously published reports, this is probably the only reliable way to decide the appropriate dose for patients, also when treated in some “off label” clinical situations.

Gender and age apparently do not have any relevance to the clinical benefit of pre-treatment with omalizumab in patients at risk of severe side effects from VIT; also, the presence of mastocytosis associated with specific IgE to BV seems to be unrelated to the duration of omalizumab treatment and to the overall improved tolerance to VIT. The two patients showed an appreciable benefit after omalizumab treatment both in terms of efficacy in reducing asthma severity and in allowing a better tolerance to ultra-rush BVIT, gaining immunization to occasional bee stings.

The above reported cases confirm that omalizumab may be a good therapeutic option to prevent reactions to immunotherapy in patients, even adolescents, undergoing BVIT with severe asthma. Since the high risk of anaphylaxis to VIT is demonstrated in many patients and documented in several clinical cases, the opportunity of pre-treatment or co-treatment for a variable period of time should be seriously considered. The promising results obtained suggest a more structured investigation. Furthermore, the combination of omalizumab and BVIT is a valuable solution for patients who do not tolerate BVIT at first.