Ulrich R. Müller

Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: Importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity

BACKGROUND Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting. METHODS In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models. RESULTS Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction. CONCLUSION In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety

Venom immunotherapy (VIT) for Hymenoptera allergy is accepted as safe and effective. However, widely varying success rates and frequencies of side effects are reported. Differences between various Hymenoptera species could account for these diverging results. We therefore analyzed 205 patients with a history of systemic allergic reactions to either honeybee (148 patients) or yellow jacket stings (57 patients) during VIT. All patients had a positive skin test to the respective venom before VIT, were monitored for side effects of VIT, and submitted to a sting challenge while they were receiving VIT. Patients with honeybee-venom allergy had a higher sensitivity in both skin tests (p less than 0.05) and RAST (p less than 0.001) than patients with yellow jacket-venom allergy. They developed systemic side effects to VIT injections significantly more often (41% versus 25%; p less than 0.01) and also reacted more frequently to the sting challenge (23% versus 9%; p less than 0.01) than patients with yellow jacket-venom allergy. We conclude that results obtained from studies on the allergy to one Hymenoptera venom cannot be extrapolated to allergies to other Hymenoptera venoms.

Predictive value of venom‐specific IgE, IgG and IgG subclass antibodies in patients on immunotherapy with honey bee venom

Sixty‐seven patients with a history of severe systemic reactions following honey bee stings were treated by immunotherapy (IT) with honey bee venom. During maintenance therapy all were submitted to a sting challenge under clinical conditions. 15 developed mostly minor symptoms of a systemic reaction while 52 showed only a local swelling at the sting site. Phospholipase A2‐specific IgE, IgG and IgG subclass serum antibodies were estimated in samples obtained before IT and immediately before the challenge. Specific IgE decreased in reactors and in non‐reactors. There was no difference between the two groups at any time. Specific total IgG, IgG1 and IgG4 increased in both reactors and non‐reactors during IT. An early increase of specific IgG1, was observed while specific IgG4 remained elevated throughout the treatment. Specific total IgG was higher in reactors than non‐reactors before the challenge, specific IgG1 higher in reactors before treatment and specific IgG4 higher in reactors than non‐reactors both before treatment and before challenge. In the individual patient, no single antibody estimation or combination of various antibodies was predictive of the outcome of a sting challenge.

Long-term protection after stopping venom immunotherapy: Results of re-stings in 200 patients

BACKGROUND Venom immunotherapy (VIT) protects most patients allergic to Hymenoptera stings while booster injections are continued. Few data on long-term protection after discontinuation of treatment are available. OBJECTIVE We sought to investigate protection from re-stings over a prolonged period after stopping VIT. METHODS Re-sting data were obtained from 200 of 322 patients in whom VIT had been stopped between 1988 and 1992 after a duration of at least 3 years. The 25 (12.5%) patients who again developed systemic allergic reactions were compared with 50 matched patients without re-sting reactions. Clinical data and diagnostic parameters (i.e., skin sensitivity and specific IgE and IgG) were studied. RESULTS Of the 25 patients who had re-sting reactions, 19 had been treated with bee venom (relapse rate, 15.8%), and six had been treated with Vespula venom (relapse rate, 7.5%). About half of the re-sting reactions occurred on the first resting after stopping VIT. Most of these reactions were mild, whereas the majority of reactions occurring after repeated re-stings were severe. When re-sting reactions were related to the total re-stings per year, an accumulation of sting reactions was observed in years 3 to 5 after stopping VIT. Patients with re-sting reactions had been receiving VIT for a significantly shorter duration (43.35 months) than those with continued protection (54.65 months) (p < 0.01). Of the diagnostic parameters, only a negative intracutaneous skin test at 10(-3) gm/L predicted long-term protection reliably. CONCLUSION Venom immunotherapy of 3 to 5 years duration induces long-term protection in most patients. In rare occasions severe re-sting reactions may, however, occur, especially after repeated re-stings.

Hymenoptera sting anaphylaxis and urticaria pigmentosa: Clinical findings and results of venom immunotherapy in ten patients ☆ ☆☆ ★

BACKGROUND Occasional patients with urticaria pigmentosa and anaphylaxis after Hymenoptera stings have been described. In this situation the question arises: Is anaphylaxis IgE-mediated or induced by pharmacologic mediator release from mast cells? METHODS We investigated 10 patients with histologically confirmed urticaria pigmentosa and a history of anaphylaxis after honeybee or Vespula stings before and during immunotherapy with the respective venom. RESULTS In eight of 10 patients, an elevated serum tryptase level was found. In two of 10 patients, no venom-specific IgE could be detected by either skin tests or RAST. Five patients had no detectable venom-specific serum IgE, and in the remaining patients the level was low (<1 Phadebas RAST unit). Venom immunotherapy was well tolerated and caused only one mild systemic reaction in a patient during the dose increase phase. Six patients were re-stung while receiving venom immunotherapy: only one had a mild systemic reaction (angioedema) after a Vespula sting. CONCLUSION Anaphylactic symptoms after Hymenoptera stings in patients with urticaria pigmentosa are most often IgE-mediated but can occasionally be observed in the absence of IgE sensitization to venom allergens. Venom immunotherapy can be safely and successfully used in patients with urticaria pigmentosa and sting anaphylaxis.

The sting challenge test in Hymenoptera venom allergy Position paper of the subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology

Ruëff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996: 51: 216–225.

Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.

BACKGROUND Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. METHODS In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. RESULTS Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. CONCLUSION Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT.

IgE to recombinant allergens Api m 1, Ves v 1, and Ves v 5 distinguish double sensitization from crossreaction in venom allergy

Diagnostic tests in patients with Hymenoptera venom allergy are frequently positive to venoms of both honey bee and wasp (Vespula). Component‐resolved analysis with recombinant species‐specific major allergens (rSSMA) may help to distinguish true double sensitization from crossreactivity.

Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils

Background Rapid clinical tolerance can be induced over several hours by very fast bee venom immunotherupy (VIT) protocols.

Reduction of side effects from rush‐immunotherapy with honey bee venom by pretreatment with terfenadine

In a double‐blind placebo‐controlled trial on 52 patients with bee venom allergy we studied the effect of a pretreatment with terfenadine 120 mg twice daily on the occurrence of local and systemic allergic side effects from rush‐immunotherapy. Large local reactions were significantly reduced by terfenadine pretreatment (P < 0.01), while systemic side effects were observed with similar frequencies in both groups. Analysis of individual systemic allergic manifestations showed that cutaneous symptoms like itching (P < 0.025) and urticaria/angioedema (P < 0.05) were significantly reduced, while respiratory or cardiovascular symptoms were not influenced. A lower consumption of additional anti‐allergic medication was found during terfenadine pretreatment (p < 0.05). Pretreatment with antihistamines during immunotherapy may thus be helpful in the management of patients with cutaneous side effects.