Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy

The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side-effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side-effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2].     

Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy

BACKGROUND: Mastocytosis and/or elevated basal serum tryptase may be associated with severe anaphylaxis. OBJECTIVE: To analyse Hymenoptera venom-allergic patients with regard to basal tryptase in relation to the severity of sting reactions and the safety and efficacy of venom immunotherapy. METHODS: Basal serum tryptase was measured in 259 Hymenoptera venom-allergic patients (158 honey bee, 101 Vespula). In 161 of these (104 honey bee, 57 Vespula), a sting challenge was performed during venom immunotherapy. RESULTS: Nineteen of the 259 patients had an elevated basal serum tryptase. Evidence of cutaneous mastocytosis as documented by skin biopsy was present in 3 of 16 patients (18.8%). There was a clear correlation of basal serum tryptase to the grade of the initial allergic reaction (P<0.0005). Forty-one of the 161 sting challenged patients reacted to the challenge, 34 to a bee sting and 7 to a Vespula sting. Thereof, 10 had an elevated basal serum tryptase, i.e. 1 (2.9%) of the reacting and 2 (2.9%) of the non-reacting bee venom (BV) allergic individuals, as compared to 3 (42.9%) of the reacting and 4 (8%) of the non-reacting Vespula venom-allergic patients. Thus, there was a significant association between a reaction to the sting challenge and an elevated basal serum tryptase in Vespula (chi2=6.926, P<0.01), but not in BV-allergic patients. Systemic allergic side-effects to venom immunotherapy were observed in 13.9% of patients with normal and in 10% of those with elevated basal serum tryptase. CONCLUSIONS: An elevated basal serum tryptase as well as mastocytosis are risk factors for severe or even fatal shock reactions to Hymenoptera stings. Although the efficacy of venom immunotherapy in these patients is slightly reduced, most of them can be treated successfully. Based on currently available data, lifelong treatment has to be discussed in this situation.     

Venom immunotherapy in patients with allergic reactions to insect stings

Introduction: Allergy to Hymenoptera (Apis mellifera, Vespula species, Polistes species, Vespa crabro) venom can be safely and effectively treated by venom immunotherapy (VIT), which in the 40 years since its introduction has been able to prevent reactions to stings, and to treatment as well, though systemic reactions, occasionally severe, are possible.

Areas covered: We reviewed the recent literature on VIT by searching in PubMed for the terms ‘venom immunotherapy’ and ‘Hymenoptera venom immunotherapy’ to highlight the current status of VIT and the likely development in the coming years.

Expert commentary: VIT, provided the correct choice of the venom and adequate venom preparations and maintenance doses are used, is a treatment of great value in preventing systemic reactions to Hymenoptera stings. A 5-year duration ensures a prolonged tolerance to stings following VIT discontinuation, unless patients suffer from mastocytosis. In fact, due to reports of fatal reactions after stopping VIT, patients with mastocytosis, or with very severe reactions to stings, need an indefinite duration of treatment.     

Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma

Background The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side-effects.
Objective The aim of this study was to study the effect of omalizumab, a monoclonal anti-IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy.
Methods A randomized, double-blind, placebo-controlled, multi-centre trial was performed to assess the efficacy and safety of omalizumab (Xolair^®) vs. placebo in combination with depigmented SIT (Depigoid^®) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use.
Results A total of 140 patients (age 11–46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% ( P =0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity ( P =0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P =0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P =0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P =0.0537). Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.
Conclusion Combination of omalizumab with SIT for treatment of patients with SAR and co-morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.     

Serum concentration of baseline mast cell tryptase: evidence for a decline during long‐term immunotherapy for Hymenoptera venom allergy

Background Baseline serum mast cell tryptase concentration (BTC) is thought to reflect the constitutive mast cell load or activity of an individual patient. Little is known about the individual stability of BTC during long‐term venom immunotherapy (VIT). Objective To investigate the intra‐individual stability of BTC over time in patients with Hymenoptera venom allergy. Methods Three hundred and two patients were studied. BTC was measured before and at least twice during VIT. At least 4 weeks lay between BTC measurements and the most recent field sting, in‐hospital sting, or preceding venom injection. Multifactorial mixed linear models were used to analyse BTC changes over time. Results Median observation time was 4.2 years (range 2–12 years). Before VIT, the median BTC was 6.8 μg/L (range 1.14–177 μg/L). The median coefficient of variation (CV) over time was 15.3% (range 1.9–63.8%). The median CV was significantly smaller in patients presenting with an elevated BTC (>11.4 μg/L) than in patients with a normal BTC (11.4%, range 2.6–39.5%; vs. 17.6%, range 1.9– 63.8%; P<0.001). During VIT and after adjusting for age and gender, we found a slight but significant decrease of BTC over time (2.5% per year, 95% confidence interval 2.0–3.0%, P<0.001). Conclusion Individual variation of BTC during VIT does not rise when BTC is increased before therapy. VIT is associated with a small, but continuous decrease of BTC over time possibly indicating a dampened mast cell function or a decline in mast cell burden. Cite this as: S. Dugas‐Breit, B. Przybilla, M. Dugas, A. Arnold, G. Pfundstein, H. Küchenhoff and F. Ruëff, Clinical & Experimental Allergy, 2010 (40) 643–649.     

Survey on practice of venom immunotherapy in France

Introduction

Venom immunotherapy (VIT) is the only efficient prevention for sting-induced anaphylaxis, but its application is not without risks and needs precautions and standardization. European guidelines were proposed in 2005, but recent practice surveys and more recent knowledge raise the need for an update. The aim of this study was to analyze VIT practices in France, based on previous surveys in Europe but also extended to outcome event management.

Material and methods

A paper questionnaire was sent widely to persons involved in venom treatment.

Results

Eighty-six responses could be included from physicians actively involved in VIT induction evenly distributed in France. The survey shows that VIT was engaged from grade III down to grade I reactions, starting preferentially with the ultra-rush protocol. Premedication was used by 42% only and risks induced by co-treatment with β-blockers were well known but not with angiotensin-converting enzyme inhibitors. However, side effects were very variably managed from arrest to enhancement in doses, time-delay or duration. Similarly, we observed a large discrepancy in treatment evaluation (skin tests, biology, timing and interpretation), decision making for treatment termination (when and how long to be prolonged) and post-treatment follow-up (adrenaline kit, event record) as well as procedures in case of late relapse (new induction, different doses).

Conclusions

Our study shows that most recommendations were fully or partially followed and may need reminding, but many points need to be completed or updated with new tools and knowledge acquired during the last 10 years.     

Safety of Hymenoptera venom rush immunotherapy

We studied 97 consecutive patients who had received Hymenoptera venom rush immunotherapy in our department. There were 53 males and 44 females, whose mean age was 46 years (8–74 years). Most study patients had experienced severe anaphylaxis induced by a Hymenoptera sting: the reaction was Müller stage IV in 48 patients. Skin tests were positive for Vespula venom in 85 cases, Polistes venom in 23, and bee venom in 23. Radioallergosorbent test values exceeded 0.70 kIU/1 in 60 cases. Immunotherapy was performed with Vespula venom alone in 73 cases, bee venom alone in five cases, and both Vespula and bee venom in 19 cases. A cutaneous reaction was seen at the injection site in most patients. Four patients also had skin manifestations in areas remote from the injection site. Blood pressure elevation was seen in 11 patients, moderate hypotension in two, rhinitis in one, asthenia or headache in seven, visual disorders and vertigo in two, and transient dyspnea in two. Our protocol has proved very safe, epinephrine never being required in the 97 reported cases.     

CD28 expression is increased in venom allergic patients but is not modified by specific immunotherapy

Background Recognition of antigen bound to the major histocompatibility complex by the T cell receptor is insufficient to lead to T cell proliferation and effector function, which require co-stimulatory signals, such as those resulting from the interaction of CD28 expressed on T lymphocytes and CD80/CD86 expressed on APCs. Lack of interaction between these accessory molecules during antigen stimulation leads to a state of antigen-specific lymphocyte unresponsiveness. Previous studies have shown that rush venom immunotherapy decreases venom-specific T cell proliferation very early after the initiation of the rush. Objective In order to see whether this hyporeactivity was associated with a down regulation of accessory molecules, we studied CD28 surface expression on T lymphocytes from 10 non-atopic controls and from 10 non-atopic patients undergoing rush venom immunotherapy. Methods Peripheral blood samples were collected before the rush (day 0), at the end of the rush (day 1), at day 15 and at day 45. CD28 expression was analysed using flow cytometry with double labelling of the CD4⁺ and CD8⁺ lymphocyte subpopulations. Results At baseline CD28 was expressed at a higher level on T lymphocytes from allergic patients than from control subjects (P < 0.04), and in particular on the CD8 subset (P < 0.01), reflecting a decrease in the suppressive CD8⁺CD28^– subpopulation. No changes were found in the percentages of total CD28⁺ T cells, CD4⁺ CD28⁺ or CD8⁺CD28⁺ cells at the different time points after the initiation of immunotherapy. Conclusion These results suggest that the CD28 pathway is probably involved in the development of allergic reactions, but at least at the phenotypic level, CD28 expression remained unchanged after rush venom immunotherapy.     

EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy

Hymenoptera venom allergy is a potentially life‐threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic‐allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life‐threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H₁‐antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence‐based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta‐analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom‐allergic children and adults to prevent further moderate‐to‐severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence‐based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence.     

Immunohistochemical analysis of late local skin reactions during rush venom immunotherapy.

During rush venom immunotherapy (VIT), about 65% of patients develop large local reactions (LLR) at the application site that last for at least 24 h. However, LLR subside during long-term treatment. To learn more about the provenance of infiltrating cells in late, local skin reactions during VIT, we analyzed the skin infiltrates of 23 Hymenoptera venom (HV)-allergic patients. Punch biopsies were obtained 24 h after s.c. injection of HV allergens from 23 HV-allergic patients and five nonallergic controls. Seven patients did not show LLR at the beginning of VIT. Ten patients had LLR when the dose of HV allergens was increased. Six patients showed reduced LLR after long-term treatment. Immunoenzymatic labeling of the cryostat sections with a panel of monoclonal antibodies was performed by the APAAP method. S.c. application of HV allergens induced a perivascular and periadnexial cutaneous mononuclear cell infiltrate consisting mainly of CD4⁺, CD45RO⁺, and HLA-DR⁺ cells in patients without clinically apparent LLR. In contrast, LLR were associated with a significant increase in total cells, CD4+ cells, CD8+ cells, CD11c⁺ cells, EG2⁺ cells, NP57⁺cells, HLA-DR⁺ cells, CD45RO⁺ cells, CD45RA⁺ cells, CD23+ cells, and CD25⁺ cells (P < 0.001). Decreased LLR after long-term VIT was correlated with a significantly reduced recruitment of CD4⁺ cells, EG2⁺ cells, and CD23⁺ cells as compared to LLR in the course of dose increases (P<0.05), whereas the number of CD8+ cells, CD11c⁺ cells, NP57⁺ cells, and CD25⁺ cells remained high. Our data suggest that s.c. injections of HV allergens attract CD4⁺ helper T cells, of both the naive (CD45RA⁺) and memory (CD45RO⁺) phenotypes, to the allergen application site. LLR represent delayed allergic rather than toxic reactions to HV components and might be relevant to the development of clinical protection during VIT.     

High sensitivity of basophils predicts side-effects in venom immunotherapy

BACKGROUND: Systemic side-effects of venom immunotherapy (VIT) represent a considerable problem in the treatment of patients allergic to Hymenoptera venom. We examined the hypothesis whether basophil responsiveness might be connected with the adverse reactions to VIT. METHODS: Basophil surface expression of activation marker CD63 induced by different concentrations of honeybee and wasp venom (0.1 and 1 mug/ml) was measured by flow cytometry in 34 patients with history of systemic anaphylactic reactions to Hymenoptera sting just before rush honeybee or wasp VIT. RESULTS: Eleven of 34 patients had systemic anaphylactic reaction (Mueller grades I-III) and one patient a large local reaction to VIT. In those 12 patients, median percentage of activated basophils after stimulation with VIT-specific venom in concentration of 0.1 microg/ml was 99% (range: 17-195) of value reached with stimulation with 1 microg/ml. Side-effects occurred in all patients with 0.1/1 ratios over 92% (eight of 12). In contrast, in 22 patients with no side-effects, the median 0.1/1 ratio was 25% (range: 2-92). These concentration-dependent activation ratios were significantly different between the groups with and without side reactions (P < 0.0001). We also show significant positive correlation of the occurrence/clinical grade of the side-effects with individual ratios of CD63 basophil response (r = 0.73, P < 0.0001). CONCLUSION: The results suggest that increased basophil sensitivity to allergen-specific in vitro stimulation is significantly associated with major side-effects of VIT.     

Ultra rush bee venom immunotherapy does not reduce cutaneous weal responses to bee venom and codeine phosphate

Background rapid administration of bee venom in cumulative doses exceeding the quantity contained in one bee sting is well tolerated by most of the patients during 3.5 h of ultra-rush bee venom immunotherapy (VIT). The mechanism of this tolerance is unknown. Objective The aim of the study was to verify the hypothesis that either slow mediator depletion of mast cells or blockade of their surface receptor mechanisms by increasing doses of allergen might be the major mechanisms of tolerance induced by ultra-rush VIT. Methods Nine bee venom allergic patients with a history of severe systemic reactions after a bee sting, positive skin tests and bee venom specific serum IgE antibodies were treated as follows: on the first day a cumulative dose of 111 μg was administered over 3.5 h under intensive care conditions. Further injections were given on day 7, day 21 and thereafter at 4 week intervals, Intradermal tests with codeine phosphate (nonspecific mast cell degranulation) and bee venom were performed before the initiation of VIT and 30 min after the last injection on the same day as well as before the subsequent bee venom injections. Results No significant changes of skin reactivity to both codeine phosphate and bee venom were observed on day I (before initiation of VIT and after the last injection on the same day). Conclusions Ultra-rush VIT does not induce mediator depletion or surface receptor blockade in skin mast cells.