Repeated anaphylactic shocks during bee venom immunotherapy and successful continuation of treatment after vaccine change

INTRODUCTION

In Central Europe, Hymenoptera venom allergy is mainly triggered by honeybee or Vespula spp stings. They manifest with the possibility of serious issues such as respiratory and cardiac arrest [1]. It is estimated that 0.3% to 8.9% of people stung by Hymenoptera develop systemic symptoms [2]. They occur more frequently in patients allergic to bee venom and with mastocytosis [3].

CASE REPORT

A 75-year-old male amateur beekeeper experienced his first anaphylactic reaction after a forearm bee sting at the end of 2018 with symptoms corresponding to grade IV of Mueller’s classification [4]. The patient’s specific immunoglobulin E (sIgE) level for bee venom was 6.38 KU/I with no detectable sIgE for wasp or hornet venom. The intradermal test, component-specific, and non-component test results are presented in Tables 1 and 2. In 2019 the patient initiated allergen-specific immunotherapy with the Venomenhal biene (HAL Allergy, Netherlands) product in the ultra-rush protocol (Tables 3 and 4). He suffered from arterial hypertension, persistent atrial fibrillation, coronary artery disease, and obesity. He took acenocoumarin, atorvastatin, perindopril, indapamide, amlodipine, potassium, and magnesium. The patient had no other diagnosed allergies. The tryptase concentration measured before immunotherapy was 11.1 μg/l (normal range up to 11.4 μg/l).

In October 2022 the patient returned for the next scheduled maintenance dose. 10 minutes after the injection (100 μg), the patient experienced symptoms of anaphylaxis characterized by loss of consciousness, breathing difficulties, and a drop in blood pressure to 70/45 mm Hg, which resolved after the administration of 1 mg of intramuscular adrenaline and intravenous electrolyte fluids. Elevated tryptase levels in the serum (27.80 μg/l) measured approximately 20 minutes after the event, confirmed the anaphylaxis. It was decided to discontinue immunotherapy temporarily.

After a 2-month break and replacing perindopril (angiotensin-converting-enzyme (ACE) inhibitor) with losartan (angiotensin II receptor blocker), an attempt was made to resume immunotherapy in the ultra-rush protocol. The administration of the fifth dose of immunotherapy (30 µg with a cumulative dose of 61.1 µg) led to another anaphylactic reaction. The symptoms included numbness of the mouth, dizziness, a blood pressure of 70/50 mm Hg, a pulse rate of 70, and a saturation level of 85% with no signs of airway obstruction. Immediate administration of intramuscular adrenaline (1 mg), intravenous antihistamine (2 mg of clemastine), glucocorticoid (250 mg of methylprednisolone), and electrolytes normalized vital parameters. The decision was made to discontinue the procedure.

The two anaphylactic reactions described were the only adverse events of VIT in this patient.

In control tests a few weeks before resuming desensitization, an increase in basal tryptase levels was observed (12.6 μg/l with a normal range of up to 11.4 μg/l). Considering the rarity of recurrent anaphylactic reactions during VIT, systemic mastocytosis was suspected despite the lack of other characteristic symptoms. Laboratory testing did not confirm this diagnosis. Basophil activation tests confirmed a specific sensitivity to bee venom (54.7% activation) while ruling out a reaction to wasp venom (0.0% activation).

Four months after the last anaphylactic reaction an attempt was made to resume immunotherapy with Alutard SQ (ALK Abello, Denmark) using a conventional protocol. After 3-hour observation, no local or general adverse effects were observed. The patient received subsequent doses of immunotherapy without any reported issues, eventually reaching the maintenance dose. The patient has been taking maintenance doses regularly without complications.

DISCUSSION

Available publications indicate the efficacy of venom immunotherapy (VIT) in preventing systemic allergic reactions to stings in patients with a history of such events [5] and a likely positive impact on the quality of patients’ lives related to their health status [6].

The clinical case illustrates the importance of an individualized approach to the patient during VIT and preparation for potential complications during the treatment. Recurrent systemic anaphylaxis may complicate reaching the maintenance dose, requiring consideration of treatment plan changes and a deeper diagnostic investigation [5].

Publications suggest that the safety profile of VIT in accelerated schemes is comparable to conventional VIT. Accelerated protocols are more convenient and reduce the time needed to achieve antigen tolerance and the cost of therapy [7, 8]. Therefore, the second attempt to initiate immunotherapy was also undertaken in the ultra-rush protocol. Notably, the first anaphylactic reaction occurred during the administration of the maintenance dose, so the immunotherapy protocol did not play a significant role. The choice of the conventional regimen for the third initiation of VIT, although difficult for organizational reasons (weekly 1-day hospitalizations at the beginning of therapy), was dictated by recommendations of the summary of product characteristics of Alutard SQ [9], in which the conventional regimen is the only one mentioned. This is likely due to Alutard SQ’s aluminum hydroxide adjuvant, causing the allergen contained in the vaccine to be released slowly in a depot form [10]. Studies indicate this substance to be associated with fewer generalized reactions [11].

The attempt to initiate immunotherapy with the same product (Venomenhal biene) despite the first anaphylactic reaction was based on the suspicion that the reaction had occurred due to the patient taking an ACE inhibitor and that changing the treatment would help avoid further adverse events. Although some sources report that the use of ACE inhibitors does not affect the safety or effectiveness of VIT [12], the summary of product characteristics of Venomenhal biene mentions the potential risk of adverse reactions during VIT in people treated with these drugs [13].

The literature indicates that the frequency of adverse reactions during VIT in patients with mastocytosis may be higher than in the general population [14]. To diagnose systemic mastocytosis, one major criterion (presence of multifocal clusters of spindled mast cells in the bone marrow with > 15% of mast cells in clusters) and one minor criterion or at least three minor criteria must be met. Minor criteria are abnormal mast cell CD25 expression, presence of KITD816V mutation, presence of > 25% atypical mast cells, and a consistently elevated basal tryptase concentration above 20 μg/l [15], as the tryptase is considered the major protease released during mast cell activation [16]. Despite lower values of the last parameter, its increase compared to the values from the beginning of the treatment and repeated anaphylactic reactions during VIT were the basis for performing diagnostics for mastocytosis. The diagnosis was excluded.

Based on the good tolerance of immunotherapy after changing medical products, a suspicion of hypersensitivity to one of the components in the first vaccine was made. Venomenhal biene contains human albumin and mannitol that are not present in Alutard SQ. The literature confirms that mannitol can induce anaphylactic reactions [17]. Another patient undergoing diagnostic testing for anaphylactic reactions during VIT was confirmed to be hypersensitive to human albumin [18]. Due to funding limitations, further diagnostics for hypersensitivity to other vaccine components has not been implemented, however, it may constitute an important diagnostic clue in similar cases.