Time course of serum inhibitory activity for facilitated allergen–IgE binding during bee venom immunotherapy in children

Background Immunotherapy for bee venom allergy is effective and provides long‐term protection. Venom‐specific IgG4 levels are increased but with no correlation with clinical improvement. Following grass pollen immunotherapy, elevation of antigen‐specific IgG4 is accompanied by increases in IgG‐dependent serum inhibitory activity for IgE‐facilitated binding of allergen–IgE complexes to B cells. As this ‘functional’ assay of inhibitory antibodies may be more predictive of clinical efficacy, we investigated the time course of serum inhibitory activity for IgE‐facilitated antigen binding during venom immunotherapy (VIT) in children and following 2 years of VIT withdrawal. Methods Ten bee venom‐allergic children (mean age: 9.3 years; m/f, 7/3) with moderate to severe allergic reactions to bee stings received VIT. A separate group of seven children (mean age: 14 years; m/f, 5/2) were investigated 2 years after VIT withdrawal. Ten age‐ and gender‐matched children served as non‐allergic controls. Allergen‐specific serum IgG4 and IgE levels were measured by ELISA at baseline, after 2 years of VIT and 2 years after VIT withdrawal. Serum inhibitory activity was assessed using the facilitated‐allergen binding (FAB) assay. Results Sera obtained during VIT significantly inhibited allergen–IgE binding to B‐cells (pre‐treatment=104±23%; 2 years=46±15%; P<0.001) when compared with sera obtained after treatment withdrawal and sera from normal controls. In parallel to FAB inhibition during VIT, significantly higher IgG4 levels were noted after immunotherapy (pre‐treatment=8.6±2.3 AU; 2 years=26.7±3.5 AU; P<0.001) compared with those observed after withdrawal and in the controls. In contrast, progressively lower IgE concentrations were observed compared with pre‐treatment (44±7 AU) in sera obtained after 2 years of VIT (25±5 AU; P<0.01) and 2 years following the withdrawal of VIT (10±3 AU; P<0.05). Conclusions In contrast to grass pollen immunotherapy, the persistent decline in venom‐specific IgE levels, rather than serum inhibitory activity for FAB, may be more relevant for long‐term clinical efficacy of VIT.     

Wasp venom immunotherapy changes IgG antibody specificity

Background The evolution of the IgG response during venom immunotherapy (VIT) has been previously investigated in terms of antibody titres and subclasses. Objectives The present work studied the evolution of IgG antibody fine specificity in wasp allergic patients treated with rush VIT. Methods Antibody specificity was evaluated in 51 wasp allergic patients in competitive ELISA using streptavidin biotin technology. Patients were tested before and during specific rush immunotherapy (at 15 days, 6 months, 12 months) and compared with 44 patients treated by venom injections for at least 2 years. Results The capacity of sera to prevent the antigen binding of pooled IgG from allergic patients changed rapidly with mean percentage inhibitions (± sd) falling from 70 ± 11–51 ± 18% after 15 days of treatment (P < 0.001 by one way anova). Similarly, the antigen binding capacity of pooled IgG from VIT patients was differently prevented by sera with mean percentage inhibitions increasing from 37 ± 12–65 ± 8 after 15 days of treatment (P < 0.0001 by one-way anova). Conclusions The immunodominance pattern of IgG epitopes recognized on wasp venom antigens by sera from wasp allergic patients changes soon after initiating rush VIT. Further studies will indicate whether, instead of measuring IgG titres, this marked change could be used as the basis of a new test for monitoring the outcome of VIT.     

Risk factors and indicators of severe systemic insect sting reactions

Hymenoptera venom allergy ranks among the top three causes of anaphylaxis worldwide, and approximately one-quarter of sting-induced reactions are classified as severe. Fatal sting reactions are exceedingly rare, but certain factors may entail a considerably higher risk. Delayed administration of epinephrine and upright posture are situational risk factors which may determine an unfavorable outcome of the acute anaphylactic episode and should be addressed during individual patient education. Systemic mastocytosis and senior age are major, unmodifiable long-term risk factors and thus reinforce the indication for venom immunotherapy. Vespid venom allergy and male sex likewise augment the risk of severe or even fatal reactions. Further studies are required to assess the impact of specific cardiovascular comorbidities. Available data regarding potential effects of beta-blockers and/or ACE inhibitors in coexisting venom allergy are inconclusive and do not justify recommendations to discontinue guideline-directed antihypertensive treatment. The absence of urticaria/angioedema during sting-induced anaphylaxis is indicative of a severe reaction, serum tryptase elevation, and mast cell clonality. Determination of basal serum tryptase levels is an established diagnostic tool for risk assessment in Hymenoptera venom-allergic patients. Measurement of platelet-activating factor acetylhydrolase activity represents a complementary approach but is not available for routine diagnostic use.     

Type-III interferons and rheumatoid arthritis: Correlation between interferon lambda 1 (interleukin 29) and antimutated citrullinated vimentin antibody levels

Aim: To assess serum type III or lambda (λ) interferons (IFN) levels and its clinical and laboratory associations in rheumatoid arthritis (RA). Methods: A cross-sectional study including 43 patients with RA (86% females; age 45.3?±?10.3 years) and 43 healthy individuals was performed. Clinical data including disease activity, acute-phase reactants, rheumatoid factor and anticyclic citrullinated peptide (anti-CCP) antibodies were collected. Serum IFNλ1, IFNλ2, IFNλ3, CXCL8 and anti-mutated citrullinated vimentin (anti-MCV) antibody levels were measured. Results: Patients with RA had higher IFNλ1 (113.5?±?118.6?pg/mL versus 55.9?±?122.3?pg/mL; p?<?0.0001) and IFNλ2 (245.4?±?327.7?pg/mL versus 5.1?±?11.0?pg/mL; p?=?0.009) levels than controls, but not IFNλ3 levels. Notably, IFNλ1 levels were found to be higher in both patients with active disease (124.9?±?135.9?pg/mL; p?<?0.001) and quiescent disease (99.0?±?93.7?pg/mL; p?<?0.01), while IFNλ2 levels were higher only in patients with active disease (264.0?±?356.1?pg/mL; p?=?0.02). A noteworthy association between serum IFNλ1 levels and anti-MCV antibody titers (Spearman's rho coefficient 0.36, 95% CI 0.36 to 0.61; p?=?0.02) was observed. Conclusion: Serum IFNλ1 and IFNλ2 levels are abnormally elevated in patients with RA and the former are linearly associated with circulating anti-MCV antibody levels. These results may place type-III IFN as an attractive new therapeutic target in RA.     

Decreased Proinflammatory Cytokines Production in Children with Complicated Parapneumonic Pleural Effusion after Intrapleural Fibrinolytic Treatment

Intrapleural fibrinolytic therapy (IFT) provides clinical benefit in the treatment of complicated pleural parapneumonic effusion (CPE). Whether IFT influences the proinflammatory cytokines production and fibrinlytic activity is currently unclear. Therefore, we collected pleural effusion samples from CPE patients with IFT (study group) and patients without IFT (control group). A membrane human inflammatory cytokines array kit was used to compare the difference of targeted cytokine production between these two groups. Enzyme-linked immunosorbent assay (ELISA) methods were used for quantitative analysis of targeted cytokines and fibrinolytic enzymes. The results showed there were no significant differences between the study (n = 16) and control (n = 14) groups in patients’ demographic data. After fibrinolytic therapy, the patients in the study group had significant lower plasminogen activator inhibitor (PAI) level (732.36?±?254.09 ng/mL vs 1,509.36?±?1,340.11 ng/mL, p?<?0.05) and higher urokinase plasminogen activator (u-PA) level (75.56?±?41.70 ng/mL vs 6.87?±?5.07 ng/mL, p?<?0.05) than they did before treatment. Moreover, the tissue inhibitors of metalloproteinase-2 (TIMP-2) (1,560.03?±?403.49 pg/mL vs 3,686.45?±?1,263.83 pg/mL, p?<?0.05) and inflammatory chemokine, regulated on activation normal T-cell expressed and secreted/chemokine (C-C motif) ligand 5 (RANTES), (293.58?±?212.93 pg/mL vs 749.27?±?53.79 pg/mL, p?<?0.05), were also significantly lower in the study group after fibrinolytic therapy, but not in the control group. In conclusion, intrapleural fibrinolytic treatment with urokinase could enhance fibrinolytic activity and decrease TIMP-2 and RANTES production.     

The renin angiotensin system and hymenoptera venom anaphylaxis

Components of the renin angiotensin system, namely renin, angiotensinogen, angiotensin I and II and aldosterone were measured in plasma of patients with hymenoptera venom anaphylaxis (n = 50) and healthy non-allergic controls (n = 25). Patients with a history of anaphylactic reactions to hymenoptera venom who did not undergo immunotherapy showed significantly reduced renin, angiotensinogen, angiotensin I and angiotensin II in plasma as compared with controls (P < 0.05). There was no difference in the aldosterone concentration between patients and controls. Angiotensin I, angiotensin II, renin and angiotensinogen levels were the same in male and female patients. There was also no difference in the angiotensin I, II, renin or angiotensinogen levels between young and older patients. A significant inverse correlation between the severity of clinical symptoms and the plasma levels of renin (r = -0.382, P < 0.001), angiotensinogen (r = -0.567, P < 0.0001), angiotensin I (r = -0.656, P < 0.0001) and angiotensin II (r = 0.0762, P < 0.0001) was found: the lower the levels the more severe the clinical symptoms. No correlation was found for aldosterone. Hymenoptera venom allergic patients with repeated anaphylactic reactions during hyposensitization did not tolerate the sting of a living insect (n = 6). In these patients, renin, angiotensinogen, angiotensin I and II remained significantly lower than in healthy non-allergic controls. Patients with successful immunotherapy (n = 27) who tolerated the sting of a living insect had renin, angiotensin I and II significantly higher than patients without immunotherapy. These findings suggest a possible role of the renin angiotensin system in hymenoptera venom anaphylaxis.     

The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venom by means of an in-hospital insect sting

Between 1979 and 1983 230 patients visited our clinic in connection with allergic reactions after insect stings. One hundred six patients were subjected to a diagnostic provocation test with a live insect; 86 of these patients had a history of systemic reactions and a positive skin test and RAST with insect venom. Thirty-one of these patients, including one patient with a negative RAST and another with a negative skin test, demonstrated a generalized reaction and were subjected to immunotherapy with pure insect venom. Comparison of the diagnostic data from 31 patients with reactions with those of the 57 nonreacting patients from the 86 patients aforementioned reveals that at this time only a provocation test with a live insect can provide the evidence of an allergy to insect venom leading to such a severe generalized reaction that admission to probably lifelong immunotherapy is justified. The measurement of the venom-specific IgG, the ratio of IgG/IgE, and (for bee patients) the serum antibody titer against the bee venom components phospholipase A and hyaluronidase did not improve the diagnosis of a current hypersensitivity against insect venom.     

Discontinuation of yellow jacket venom immunotherapy: Follow-up of 75 patients by means of deliberate sting challenge

Background: Venom immunotherapy is effective in preventing systemic reactions in patients with a history of an anaphylactic reaction to Hymenoptera stings. It is uncertain how long venom immunotherapy should be continued. Objective: We evaluated whether the duration of venom immunotherapy given to yellow jacket–sensitive patients related to the risk of an anaphylactic reaction to a later sting. Methods: Seventy-five yellow jacket–sensitive patients (29 male and 46 female) received a median number of three in-hospital sting challenges from a live insect in 3 subsequent years after discontinuation of venom immunotherapy. An anaphylactic reaction to one or more of the sting challenges was considered a relapse. We analyzed whether patients with and patients without a relapse differed in terms of gender, age, preimmunotherapy skin test data, preimmunotherapy level of venom-specific IgE, severity of the field-sting reaction that preceded immunotherapy, severity of the reaction to the sting challenge that preceded immunotherapy, adverse reactions to immunotherapy, changes in IgE and IgG₄ levels during immunotherapy, duration of immunotherapy, and presence of venom-specific IgE after cessation of therapy. Results: Venom immunotherapy was given for a median duration of 40 months (range, 7 to 120 months). Relapses were observed in six patients. In two of them, a rather severe anaphylactic reaction was observed after the second sting challenge. No relation was found between duration of venom immunotherapy and relapse risk. The relapse rate was higher among patients with high levels of specific IgE before and after immunotherapy. During therapy, the mean level of specific IgE decreased. This decline persisted in the 3 following years. No relapses of sting reactions were observed among patients without detectable specific IgE. Conclusion: Discontinuation of venom immunotherapy appears safe for patients with pretreatment IgE antibodies if these antibodies can no longer be detected during immunotherapy. For the remaining patients, a treatment period of 3 years may suffice. After discontinuation of immunotherapy, a clinical sting challenge can be considered to estimate the patient's current grade of hypersensitivity. (J Allergy Clin Immunol 1997;100:767-70.)     

Occupational allergy to bumble bee venom

The clinical profile of anaphylactic reactions to bumble bees is described and successful immunotherapy with honey bee venom in seven bumble bee allergic patients is reported. The cause of the high frequency of sensitization to pollen in these patients is discussed.     

Vitamin D analogs decrease in vitro secretion of RANTES and enhance the effect of budesonide

PurposeEosinophils appear to be central inflammatory cells in the pathogenesis of rhinosinusitis with nasal polyps (NP). One of the most predominantly recognized eosinophil chemoattractants is RANTES. The aim of this study was to assess the influence of vitamin D (VD) derivates on RANTES expression in the culture of nasal polyp fibroblasts.Material and methodsNP fibroblast cell cultures derived from 16 patients with NP were first stimulated with bacterial LPS and than incubated in increasing concentrations (from 10^?7M to 10^?4M) of calcitriol, tacalcitol or budesonide and in combination with one of VD derivate with budesonide in 1:1, 1:3 and 3:1 ratios. Quantitative analysis of RANTES level was conducted in culture supernatants using an ELISA method.ResultsThe highest calcitriol concentration (10^?4M) as well as tacalcitol at 10^?5M and 10^?4M reduced RANTES production significantly compared to the control (201.1pg/ml, 338.7pg/ml, 211.3pg/ml v 571.78pg/ml; p<0.05). Budesonide and calcitriol administered in 1:3 ratio and budesonide and tacalcitol in 1:1 and 1:3 reduced RANTES concentration significantly better than each of the drug used in monotherapy (p<0.05). Budesonide and tacalcitol in 1:1 and 1:3 ratios suppressed RANTES production to the lowest level (171.8±97.6pg/ml and 178.7±105.22pg/ml, respectively).ConclusionActive VD compounds via downregulation of RANTES production exert a potential role as a complementary element in the therapy of chronic rhinosinusitis with NP. Compounds consisting of budesonide and VD derivate have an advantage over both drugs used in monotherapy.     

Occupational anaphylaxis – an EAACI task force consensus statement

Anaphylaxis is a systemic allergic reaction, potentially life‐threatening that can be due to nonoccupational or, less commonly, to occupational triggers. Occupational anaphylaxis (OcAn) could be defined as anaphylaxis arising out of triggers and conditions attributable to a particular work environment. Hymenoptera stings and natural rubber latex are the commonest triggers of OcAn. Other triggers include food, medications, insect/mammal/snake bites, and chemicals. The underlying mechanisms of anaphylactic reactions due to occupational exposure are usually IgE‐mediated and less frequently non‐IgE‐mediated allergy or nonallergic. Some aspects of work‐related allergen exposure, such as route and frequency of exposure, type of allergens, and cofactors may explain the variability of symptoms in contrast to the nonoccupational setting. When assessing OcAn, both confirmation of the diagnosis of anaphylactic reaction and identification of the trigger are required. Prevention of further episodes is important and is based on removal from further exposure. Workers with a history of OcAn should immediately be provided with a written emergency management plan and an adrenaline auto‐injector and educated to its use. Immunotherapy is recommended only for OcAn due to Hymenoptera stings.     

Component-resolved diagnosis in selecting patients for yellowjacket venom immunotherapy

Background

Venom immunotherapy is effective in preventing systemic allergic reactions (SARs), but the diagnosis of venom allergy is problematic.

Simplification of intradermal skin testing in Hymenoptera venom allergic children

Background

The direct comparison between children and adults with Hymenoptera venom anaphylaxis (HVA) has never been extensively reported. Severe HVA with IgE-documented mechanism is the recommendation for venom immunotherapy, regardless of age.

Dose dependence of Hymenoptera venom immunotherapy

The clinical and immunologic efficacy of venom immunotherapy up to 50 μg maintenance doses (half the recommended dose) was examined in 23 patients with anaphylactic sensitivity to insect stings and is compared with that in two groups of patients treated with the full 100-μg recommended dose. Four of the 19 patients challenged with insect stings had mild systemic reactions not requiring treatment. This 79% clinical efficacy is significantly less than the 96% to 100% success achieved with treatment to full 100-μg maintenance doses. The venom-specific IgG antibody response to the 50-μg dose reached a level significantly lower than that observed with 100-μg doses. We conclude that the clinical and immunologic responses to venom immunotherapy are dose dependent and are more reliably complete at the recommended maintenance dose of 100 μg of each venom than at a dose of 50 μg.     

Late-onset allergic reactions, including serum sickness, after insect stings

Allergic reactions after insect stings may have a delayed onset, differing from the usual immediate anaphylactic pattern. Ten patients, aged 6 to 78 years, had allergic reactions 1 to 2 weeks after an insect sting. Six patients had had multiple stings preceding the reaction. In two instances, immediate anaphylaxis also occurred. Four of the 10 patients had serum sickness-type reactions; two other patients had more severe anaphylactic symptoms, including throat edema. All patients in this group had venom-specific IgE; four of the 10 patients had serum venom-specific IgG. Eight patients subsequently received venom immunotherapy (VIT). There have been no reactions from seven re-stings. Five patients had generalized hives starting 6 to 24 hours after an insect sting. All patients in this group had venom-specific IgE; three patients have received VIT. Two other patients developed hives, one with throat edema 3 days after an insect sting. Both patients had high titers of serum venom-specific IgE; neither patient has received VIT, one patient because of extreme sensitivity. These observations suggest that after an insect sting, patients may develop delayed-onset allergic symptoms that range from typical anaphylaxis to serum sickness and are mediated by venom-specific IgE. VIT is recommended for patients with these reactions.     

Salivary and Serum Interleukin-18 in Patients with Oral Lichen Planus: A Study in an Ethnic Chinese Population

The purpose of this study was to investigate the potential pro-inflammatory role of the cytokine interleukin (IL-18) in oral lichen planus (OLP) so as to provide a reliable and early indicator for the diagnosis of OLP. One hundred three ethnic Chinese patients with OLP were enrolled in this study, as were 48 age- and sex-matched controls. IL-18 concentrations in serum and saliva were screened by enzyme-linked immunosorbent assay. The protein content was expressed as picograms per milliliter. OLP patients showed a high-level of IL-18 expression profile in serum compared with the control group (OLP?=?21.32?±?8.26?pg/mL, control?=?12.29?±?5.11?pg/mL, P?<?0.05), and the saliva partner had significantly higher concentrations of IL-18 compared to the control (OLP?=?20.12?±?5.78?pg/mL, control?=?15.60?±?4.17?pg/mL, P?<?0.05). In patients with OLP, serum and salivary IL-18 are elevated, correlating with the severity of illness. These findings may be considered to improve the predictive or prognostic values of inflammatory cytokines for OLP and also to design possible novel therapeutic approaches.     

Hymenoptera venom allergy: time course of specific IgE concentrations during the first weeks after a sting.

Detection of IgE antibodies specific to honeybee or Vespula venoms is an important criterium firstly for the diagnosis of sensitization and secondly for the indication for a specific immunotherapy. Some authors recommend to postpone blood analysis after an insect sting for a certain time because circulating IgE antibodies might be consumed by the allergic reaction, which would result in a false-negative test outcome. We investigated IgE concentrations during the first weeks after an insect sting in 31 patients with an unequivocal history of an anaphylactic reaction after a honeybee (n = 13) or Vespula (n = 18) sting. Blood samples for analysis of specific IgE concentrations (CAP system, Pharmacia Diagnostics, Sweden) were collected within 2 weeks and 5+/-2 weeks after the insect sting. 12/13 patients with honeybee venom and 14/18 patients with Vespula venom sensitization had CAP classes 1 or higher within the first 2 weeks. Those 5 patients with CAP class 0 within the first 2 weeks had detectable IgE concentrations a few weeks later. We conclude that testing for specific IgE to hymenoptera venoms is in most cases useful even during the first 2 weeks after the hymenoptera sting. This allows early decisions on further diagnostic procedures and the therapeutic way to choose. Patients with no detectable IgE should, however, be retested after a few weeks.     

Rush Hymenoptera venom immunotherapy: a safe and practical protocol for high-risk patients

BACKGROUND: Hymenoptera venom immunotherapy in allergic patients is a well-established treatment modality for the prevention of systemic anaphylactic reactions caused by insect stings. A variety of therapy regimens exists, from conventional to rush and ultrarush modalities that operate on continuous or intermittent schedules. OBJECTIVE: The aim of this study was to report the 8-year experience with our rush venom immunotherapy regimen in predominantly high-risk patients and to compare data on safety and convenience with the results of 26 studies published from 1978 to 2001. METHODS: One hundred one patients allergic to bee, yellow jacket, or hornet venom were treated with rush Hymenoptera venom immunotherapy. Diagnosis and selection of patients for venom immunotherapy were carried out according to the recommendations of the European Academy of Allergology and Clinical Immunology. We used a 4-day regimen, and the incidence and nature of systemic reactions (SRs) were documented. Fifty-two patients were treated with honeybee venom, and 49 were treated with yellow jacket venom. RESULTS: One hundred (99%) patients reached the maintenance dose. We observed 8 injection-related SRs (0.47% of all injections given) in 7 (6.9%) patients. The number of SRs was higher in patients treated with bee venom extract (12%) compared with in patients receiving yellow jacket venom extract (2%). There was no significant difference in the risk of SRs between female and male patients. The incidence of SRs was considerably lower than the average of 17.8% reported in the literature. CONCLUSION: With a rush immunotherapy regimen over a time period of 8 years in predominantly high-risk patients, the incidence of SRs was low, despite the high number of patients with bee venom allergy, who are more likely to have side effects. Epinephrine as rescue medication was never necessary, and the regimen proved to be safe and convenient for both the patients and the medical staff.     

Expansion of circulating Foxp3+CD25bright CD4+ T cells during specific venom immunotherapy

Background Venom immunotherapy (VIT) induces long‐lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. Aim Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. Methods Fourteen hymenoptera venom‐allergic patients with severe reactions (grades III–IV) were studied before, 6 and 12 months after starting ultra‐rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA‐4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real‐time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. Results VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25^bright and/or Foxp3⁺ CD4⁺ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom‐specific IgG4/IgE ratio shift. Conclusion VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.     

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.