A 'Difficult' Insect Allergy Patient

Reliable History of a Sting, but All Testing Negative

James M. Tracy; Jonathan A. Olsen; John Carlson


Curr Opin Allergy Clin Immunol. 2015;15(4):358-363. 

In This Article

Mastocytosis and Serum Tryptase

Mastocytosis and occult mast cell disease have emerged as a surprising link in this clinical quandary of a history-positive individual, yet negative to both skin testing and in-vitro testing.[23]

The diagnostic criteria for systemic mastocytosis are discussed elsewhere,[24,25] and compared with other causes of anaphylaxis such as drugs and foods, mastocytosis has a unique importance in the management of Hymenoptera allergy.[26,27] The prevalence of clonal mast cell disease in venom-allergic patients ranges between 1 and 7.9%.[28] This has been particularly important as it relates to venom allergy diagnosis and assessing high-risk individuals for future severe reactions as well as a consideration in the duration and safety of venom immunotherapy.[29] Rueff et al. in a multicenter study of 962 Hymenoptera venom-sensitive patients looked at predictors of severe systemic anaphylaxis following a sting. Of the 962 patients, 202 (26%) had severe anaphylaxis following a field sting. The reported severity was either Mueller grade III or IV with the identified risk predictors of sting-related anaphylaxis that included patients taking angiotensin converting enzyme inhibitors; vespid allergy; male sex; and patients with baseline serum mast cell tryptase levels above 5 ng/ml.[30] Bonadonna et al. reported a correlation between systemic reaction to Hymenoptera sting and mast cell tryptase. Of 379 patients with a history of systemic insect sting reactions, 11.6% had serum mast cell tryptase levels exceeding 11.4 ng/ml. Of this group, the rate of systemic (Muller grade IV) anaphylaxis was 70.5%. Thirty-four of the patients with elevated mast cell tryptase level underwent bone marrow biopsy; of those patients, 61.8% were ultimately diagnosed with indolent systemic mastocytosis.[31] Blum et al. confirmed these findings in a 5-year retrospective study of 868 patients referred for the evaluation severe reactions to Hymenoptera stings. Of the 868 patients, 758 had both total IgE and baseline tryptase levels drawn. Baseline tryptase level (>11.4 ng/ml) was associated with severe systemic reactions (P = 0.026).[32] Additionally, because of the dramatic increase in severe sting-related anaphylaxis in patients with mastocytosis, physicians should consider occult mast cell disease in anyone with unexplained anaphylaxis, sting-related anaphylaxis, and especially an individual with a positive history of a systemic anaphylactic reaction to a Hymenoptera sting, with negative venom testing.[29]

Not all of these patients have evidence of venom-specific IgE, yet the insect sting is clearly a trigger. There may be a role for non-IgE-mediated immunologically triggered reactions and mast cell disease may provide a new optic to this challenge. Omalizumab may be an additional lens providing insights into the explanation of the history-positive venom test negative patient.[33]

Omalizumab, a humanized murine mAb, conjugates with free serum IgE that reduces binding to the high-affinity FCeRI on mast cells and basophils and may provide additional insights. Omalizumab has also been demonstrated to dramatically decrease the high affinity IgE receptor (FCeR1) on mast cell and basophils. Omalizumab also appears to stabilize mast cells making them less reactive and may be used as an adjunctive treatment in individuals with mastocytosis.[34] It may have an important role in decreasing symptoms and adverse effects of venom immunotherapy as well in individuals with non-IgE-mediated insect sensitivity and concomitant mast cell disease. Douglass et al.[35] reported in 2009 the effectiveness of omalizumab in treating systemic mastocytosis in a nonatopic patient. Kontou-Fill et al.[33] presented similar results when treating a patient with systemic mastocytosis following sting-induced, non-IgE-mediated reactions.

There appears to be a high correlation with mastocytosis when the baseline tryptase exceeds 11.4 ng/ml, suggesting that this diagnosis be entertained in patients with severe anaphylaxis from Hymenoptera and be considered in all patients with anaphylaxis related to Hymenoptera sting. There may be elements and causality to seemingly 'allergic' reactions that may not be IgE-mediated. A greater understanding of the role of omalizumab and its effect on the high-affinity FCeRI and subsequent mast cell stability may provide insight into the clinical dilemma of the history-positive venom test negative individual. In these situations, the treatment of choice would not be VIT, but rather omalizumab may be a better choice.