Clinical and immunological studies of beekeepers

Thirty-four beekeepers were interviewed and their blood assayed for the presence of antibodies reacting with bee venom, bee venom phospholipase A (PLA), and whole bee body extract. Following a bee sting, most beekeepers experienced only minimal local tissue reaction. Their serum contained high levels of total antibodies (primarily IgG) reacting to bee venom and phospholipase A. These antibody titres correlated with the frequency of bee stings. Bee venom and PLA specific IgE antibodies were present in serum of some beekeepers. Beekeepers who had experienced allergic reactions were characterized by low total antibody and high venom specific IgE antibody titres. Bee body IgE antibodies were found in varying degree and did not correlate with levels of venom IgE antibodies. There was no difference in the titres of bee body IgE in the sera of beekeepers with and without systemic reactions. The data suggest that allergic reactions are mediated by venom specific IgE and immunity is at least in part a function of other antibodies, probably primarily IgG.     

Insect sting allergy with negative venom skin test responses

BACKGROUND: In our 1976 controlled venom immuno rapy trial, 33% of 182 patients with a history of systemic reactions to insect stings were excluded because of negative venom skin test responses. There have been reports of patients with negative skin test responses who have had severe reactions to subsequent stings. OBJECTIVE: Our aim is to increase awareness about the patient with a negative skin test response and insect sting allergy and to determine the frequency and significance of negative skin test responses in patients with a history of systemic reactions to insect stings. METHODS: We prospectively examined the prevalence of negative venom skin test responses in patients with a history of systemic reactions to stings. In patients who gave informed consent, we analyzed the outcome of retesting and sting challenge. RESULTS: Of 307 patients with positive histories screened for our sting challenge study, 208 (68%) had positive venom skin test responses (up to 1 microg/mL concentration), and 99 (32%) had negative venom skin test responses. In 36 (36%) of the 99 patients with negative skin test responses, the venom RAST result was a low positive (1-3 ng/mL), or repeat venom skin test responses were positive; another 7 (7%) patients had high venom-specific IgE antibody levels (4-243 ng/mL). Notably, 56 (57%) of 99 patients with positive histories and negative skin test responses had negative RAST results. In patients with positive skin test responses, sting challenges were performed in 141 of 196 patients, with 30 systemic reactions. Sting challenges were performed on 37 of 43 patients with negative skin test responses and positive venom-specific IgE and in 14 of 56 patients with negative skin test responses and negative RAST results. There were 11 patients with negative skin test responses who had systemic reactions to the challenge sting: 2 had negative RAST results, and 9 had positive RAST results at 1 ng/mL. The frequency of systemic reaction was 21% in patients with positive skin test responses and 22% in patients with negative skin test responses (24% in those with positive RAST results and 14% in those with negative RAST results). CONCLUSIONS: Venom skin test responses can be negative in patients who will subsequently experience another systemic sting reaction. Venom skin test responses are negative in many patients with a history of systemic allergic reactions to insect stings and may be associated with positive serologic test responses for venom-specific IgE antibodies (sometimes strongly positive results). Venom skin test responses should be repeated when negative, along with a serologic IgE antivenom test. Better diagnostic skin test reagents are urgently needed.     

Comparison of the allergenic properties of bee venom and whole bee body extract

The allergenic properties of bee venom and whole bee body extract were compared by in vivo and in vitro tests. The majority of patients with known bee sting sensitivity had positive intracutaneous skin test reactions with bee venom and had bee venom specific IgE in their sera. Of seventeen patients with positive bee venom skin tests, nine had positive tests with whole bee body extract. Of thirty sera containing elevated levels of bee venom specific IgE obtained from untreated patients, fourteen sera contained whole body specific IgE but in much lower titres. In RAST inhibition experiments using both bee venom and whole bee body extract as coupling antigens, bee venom was a more potent inhibiting antigen than whole body extract. From these experiments we conclude that bee venom is a more potent allergen than whole bee body extract.     

Evaluation of decline in serum venom-specific IgE as a criterion for stopping venom immunotherapy

During a 7-year period, venom immunotherapy has been stopped in 57 patients because of a fall in IgE antibody titers to insignificant levels (RAST less than 10% STD). All patients had a history of venom anaphylaxis and elevated venom-specific IgE before therapy. Maintenance doses of 50 micrograms were administered every 4 to 6 weeks; 30 patients received yellow jacket venom, and 16 patients received honeybee venom only. Therapy was stopped after treatment from 1 to 8 years (mean 2.8 years). Repeat skin tests demonstrated an average two-log decrease in sensitivity; 35 of 55 tests remained positive at venom concentrations of less than or equal to 0.1 micrograms/ml. There were 55 re-stings in 24 patients, occurring from 3 months to 5 years after cessation of therapy, resulting in three systemic reactions. One patient, previously treated with bee venom, reacted to a yellow jacket sting. These re-sting reactors also had tolerated several other stings after therapy was stopped. Thus, the two actual reactions represent a "failure" rate of 8% per patient and 4% per sting, compared to reaction rates of 27% and 17% in patients who stopped therapy without physician advice. These data suggest that this criterion may be reliable for stopping therapy. However, subsequent tolerated re-stings may require continued patient evaluation.     

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.     

Insect allergy. Predictive value of diagnostic tests: a three-year follow-up study

One hundred and six adults with various reactions to yellow jacket (YJ), honey bee (HB) or unidentified insects (UI) were tested for allergy to insect venoms. For various reasons none received immunotherapy. Individuals completed questionnaires annually for three consecutive years and described sting reactions within the previous season. Ninety subjects completed all the questionnaires and 77 of these were re-tested at the end of the period. Nine out of 25 patients reacted with a systemic reaction when re-stung. High IgE and low IgG venom-specific antibody levels indicated an unfavourable prognosis, since eight of 11 individuals who initially presented venom-specific IgE > RAST class 2 and venom-specific IgG below detection limit had systemic reactions at re-sting. No such reactions occurred in subjects with no specific IgE and only one out of six with specific IgE as well as IgG reacted systematically. Skin prick tests (SPT) of <3mm with YJ venom 1,000 μg/ml excluded later systemic symptoms to stings, whereas larger skin reactions gave an equal chance of systemic or local reactions at re-sting. In individuals not stung by UI, YJ and/or HB the decline in venom-specific IgG and IgE was significant, median values ranging from 41% to 75% over the 3-year period. The decline was unaffected by the type of sting reaction prior to the initial test. SPT results did not change significantly. The findings are relevant when testing patients several years after their last insect sting and the results might indicate that the antibody decline is accompanied by a decrease in clinical sensitivity.     

Influence of total IgE levels on the severity of sting reactions in Hymenoptera venom allergy

BACKGROUND: Detection of specific IgE for Hymenoptera venoms and skin tests are well established diagnostic tools for the diagnosis of insect venom hypersensitivity. The aim of our study was to analyze the effect of total IgE levels on the outcome of generalized anaphylactic reactions after a Hymenoptera sting. METHODS: Two hundred and twenty patients allergic to bee, wasp, or European hornet venom were included in the study. Their specific and total IgE levels, serum tryptase levels, skin tests, and sting history were analyzed. RESULTS: In patients with mild reactions (grade I, generalized skin symptoms) we observed higher total IgE levels (248.0 kU/l) compared to patients with moderate reactions (grade II, moderate pulmonary, cardiovascular, or gastrointestinal symptoms; 75.2 kU/l) and severe reactions (grade III, bronchoconstriction, emesis, anaphylactic shock, or loss of consciousness; 56.5 kU/l; P < 0.001). Accordingly, 25% of the patients with low levels of total IgE (<50 kU/l), but no individual with total IgE levels >250 kU/l, developed loss of consciousness (P = 0.001). Additionally, specific IgE levels were related to total IgE levels: Specific IgE levels increased from 1.6 to 7.1 kU/l in patients with low (<50 kU/l) and high (>250 kU/l) total IgE levels, respectively (P < 0.001). Specific IgE levels correlated inversely to the clinical reaction grades, however, this trend was not statistically significant (P = 0.083). CONCLUSION: Patients with Hymenoptera venom allergy and high levels (>250 kU/l) of total IgE, predominantly develop grade I and grade II reactions and appear to be protected from grade III reactions. However, this hypothesis should be confirmed by extended studies with sting challenges.     

Further observations of stopping venom immunotherapy: Comparison of patients stopped because of a fall in serum venom-specific IgE to insignificant levels with patients stopped prematurely by self-choice

This study extends our experience applying the criterion of a fall in serum venom-specific IgE (RAST) to insignificant levels as an indication to stop venom immunotherapy (VIT) and compares the follow-up results with the results of re-stings in patients who stopped VIT "prematurely" by self-choice. All patients in both groups had a history of venom anaphylaxis, most with cardiovascular and/or respiratory symptoms and initial elevated serum venom-specific IgE; all patients received VIT. The groups were closely matched for age, sex, nature of initial sting reaction, and insect identification. In the group with low-level RAST titers, the duration of VIT was 6 months to 5 years (mean 2 1/2 years). Re-stings occurred from 1 month to 7 years (mean 2.2 years) after cessation of therapy. There were 75 re-stings in 41 patients with four systemic reactions (10% per patient and 5% per sting). All four reacting patients had tolerated several stings during cessation of VIT before the re-sting systemic reaction; two patients had subsequent stings with no reaction. In the group of patients who stopped VIT for other reasons, the duration of VIT was 5 months to 4 years (mean 1.8 years). Re-stings occurred from 4 months to 6 years (mean 2.1 years) after stopping therapy. There were 74 re-stings in 38 patients with seven systemic reactions in four patients (9.5% per patient and 10.5% per sting). Two of the reacting patients had tolerated stings before the re-sting reaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of the radioallergosorbent test in the diagnosis of Hymenoptera anaphylaxis

IgE antibody levels to Hymenoptera (honey bee, hornet, wasp or yellow jacket) venom or venom sac were measured in the serum of ninety-six patients with a history of immediate hypersensitivity reactions to these insect stings. Normal levels of IgE antibody were found in fourty-four of these patients tested. The severity of the systemic reaction was similar in those patients with normal and elevated IgE antibody levels, and the interval from the systemic reaction to antibody determination was also similar. In twelve patients with a definite reaction to honey bee venom, the IgE antibody was elevated in all and correlated with a positive venom skin test in nine out of the twelve. It is not possible to determine if the other patients with normal IgE antibody and a systemic reaction represent a false negative RAST value, loss of sensitivity to the Hymenoptera venom, or a lack of RAST sensitivity with some venom or venom sac antigens. Without the ready availability of venom skin tests to all Hymenoptera antigens or other in vitro tests, a definite assessment of insect anaphylaxis remains in doubt for the patient and physician.     

Sensitization following Hymenoptera whole body extract therapy

Treatment of an insect sensitive patient with Hymenoptera whole body extracts (WBE) led, on five occasions, to a serum sickness-like syndrome which did not recur after therapy was stopped. The patient was found to be sensitive by skin test, histamine release, and radioallergosorbent test (RAST) to both venom and WBE as well as to venomless bee body preparations. Subsequent therapy with honeybee and yellow jacket venoms was without sequelae, and after treatment the patient did not react to a sting. In order to assess the frequency of sensitivity to irrelevant body proteins in patients treated with WBE we carried out WBE RASTs on sera from 15 such patients and compared them with those from 15 nontreated insect-allergic patients who had similar venom-specific IgE antibody levels. None of the patients allergic to insects who had not been treated with WBE had detectable IgE anti-WBE antibodies, while about 50% of those treated with WBE had developed IgE antibodies against these proteins. It appears that sensitization to nonvenom WBE proteins in terms of the development of IgE antibody is a common result of this therapy, and, rarely, repeated challenge with this complex antigenic mixture can also lead to clinical illness.     

Clinical application of measurements of serum levels of bee venom-specific IgE and IgG

Bee venom-specific IgE and IgG antibodies were measured in the serum of beekeepers, bee-allergic persons, and normal persons infrequently stung without adverse effects. Beekeepers, who are stung frequently and relatively “immune” to bee stings, are characterized by high serum levels of IgG- and low serum levels of IgE-specific antibodies. Bee-allergic individuals have high titers of bee venom-specific IgE and generally low titers of bee venom-specific IgG. Following a bee sting, allergic individuals develop a rising titer of IgE antibodies, accompanied occasionally by a rise in IgG antibodies. Therapy with whole bee body extracts fail to effect IgE or IgG antibody titers. During the course of venom immunotherapy IgG-specific antibodies are stimulated and IgE-specific antibodies continue to decline. These observations suggest that: (1) bee sting allergy is a function of bee venom-specific IgE; (2) bee sting immunity is a function of bee venom-specific IgG; and (3) bee venom is an appropriate therapeutic antigen.     

Insect sting anaphylaxis in patients without detectable serum venom-specific IgE

Following insect sting anaphylaxis, twenty-five patients of over 500 evaluated, did not have detectable serum venom-specific IgE. Twenty-two were evaluated within 1 year of the reaction, fifteen within 6 months. Anaphylaxis occurred in six patients after their first sting exposure. The clinical features of the sting reaction were typical of the reaction occurring in insect-allergic patients with serum venom-specific IgE. Eleven of the twenty-five patients had negative venom skin tests. These observations suggest that a non-IgE mechanism may be responsible for a minority of insect sting reactions.     

Comparison of 2 maintenance doses (100 microg vs 200 microg) in Hymenoptera venom immunotherapy: influence of the maintenance dose on the immunologic response.

BACKGROUND: In Hymenoptera venom immunotherapy, the maintenance dose is usually 100 microg. However, persistent systemic reactions to sting challenges could be treated by an increase in the maintenance dose to 200 microg with success, suggesting greater efficiency. OBJECTIVE: To compare the effects of 2 monthly maintenance doses (100 microg vs 200 microg) on skin test sensitivity and venom specific IgE antibody levels. METHODS: Twenty-two patients receiving Vespula venom immunotherapy were enrolled in this retrospective study. After rush therapy, the 100-microg maintenance dose initially administered was maintained (group 1, n = 13) or was increased to 200 microg (group 2, n = 9). RESULTS: Levels of venom specific IgE antibody and skin test results measured before the onset of immunotherapy were comparable in both groups. Unlike in group 1, a maintenance dose of 200 microg resulted in significant decreases in venom specific IgE antibody levels and skin test sensitivity. CONCLUSIONS: Increasing the monthly maintenance dose to 200 microg results in a greater degree of change in venom specific IgE antibody levels and skin test sensitivity than when maintaining a 100-microg dose. Our data strengthen those of previous clinical studies showing the usefulness of a 200-microg maintenance dose in the case of clinical failure of a 100-microg dose.     

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.)     

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.     

Reproducibility of skin testing and serum venom specific IgE in Hymenoptera venom allergy.

BACKGROUND: The decision regarding an immunotherapy regimen for venom-allergic patients is based on the results of skin testing and serum venom specific IgE measurements. However, their reliability has been questioned, and their reproducibility has not been examined. OBJECTIVE: To evaluate the reproducibility and reliability of the results of skin testing and serum venom specific IgE measurement in venom-allergic patients. METHODS: Patients with a systemic reaction after an insect sting were evaluated twice, 2 to 6 weeks apart, by intradermal skin tests and by determination of serum venom specific IgE to Hymenoptera venoms. RESULTS: Thirty-five patients were evaluated 1 to 168 months (mean, 23 months) after the sting reaction. Reproducibility of skin test results for all venoms at the 2 sessions was found in 23 patients (66%). Reproducibility of venom specific IgE results for all venoms was found in 16 (59%) of 27 patients from whom 2 blood samples were available for evaluation. Concordance between skin test and venom specific IgE results for all venoms was found in 30 (51%) of 59 samples available for evaluation. CONCLUSIONS: The reproducibility of venom skin test and serum venom specific IgE results is relatively poor. It is common practice for therapeutic decisions regarding venom immunotherapy to be based on a single diagnostic evaluation. Consequently, many patients are either overtreated or undertreated. Better diagnostic methods are required in venom allergy.     

A case of anaphylaxis by ant (Ectomomyrmex spp.) venom and measurements of specific IgE and IgG subclasses.

Hypersensitivity to the stings of the Hymenoptera has been described since antiquity. The hypersensitive reactions to insect stings vary from minor skin reactions to severe and sometimes fatal anaphylaxis. Concerns about sting hypersensitivity have been increasing because of many incidents of allergic reactions of patients to the fire ant in the southern area of the United States as well as the harvester ant in some areas. We experienced one unique case with severe allergic reactions by ant of the Ectomomyrmex spp. of the subfamily Ponerinae, which is not a harvester ant. For three years the patient had been suffering from generalized allergic reactions such as anaphylaxis after the ant stings four-five attacks in a year. We determined that her reactions were due to specific IgE mediated type I hypersensitivity by the detection of a high level of specific IgE to the ant venom in her serum. The high level of specific IgG4 to the ant venom was also noted in her serum, however, the role of ant venom IgG4 was not clearly determined.     

Low specific IgE, IgG and lymphocyte reactivity in a group of patients developing anaphylaxis following a honey-bee sting

Ten patients who developed severe generalized reactions following a honey-bee sting were investigated for the presence of specific IgE and IgG antibodies, and for lymphocyte reactivity following in-vitro honey-bee venom (HBV) stimulation. Five of the patients (high responders) showed high HBV-specific IgE and IgG levels, whereas the other five patients (low responders) showed low HBV-specific IgE and IgG levels. Mononuclear cells from the high responder group incorporated significant amounts of ³H-thymidine when activated with pure bee venom, whereas insignificant lymphocyte proliferation was observed in the low-responder group. It is concluded that, amongst HBV-sensitive patients, a group of low responders exists in whom the mechanism of anaphylaxis cannot be explained.     

Allergy to venom from bee or wasp: the relation between clinical and immunological reactions to insect stings

Sixty-three patients, applying to the casualty ward after a bee or wasp sting, were tested. On the day of admission, and 4 weeks later, blood was sampled to measure specific IgE and IgG against bee and wasp venom and total IgE. Four weeks after the insect sting, all patients were examined with skin-prick test (1, 10 and 100 μg/ml), and intracutaneous test (0.05 ml of extract 1.0 μg/ml). The amount of venom-specific IgE and IgG increased significantly during the 4-week period, venom-specific IgE was most pronounced in patients experiencing the most severe clinical reactions. However, no significant correlations were found between the results of the immunological tests carried out 4 weeks after the insect sting and the clinical reaction upon the insect sting.     

Insect venom allergy: a prospective case study showing lack of correlation between immunologic reactivity and clinical sensitivity

This case report demonstrates the lack of correlation between clinical sensitivity to insect venoms and immunologic reactivity as indicated by the presence of venom-specific IgE. A 20-yr-old venom collector was monitored over a 3-yr period with measurements of venom-specific IgE (skin test and RAST) and venom-specific IgG. In the first year of venom collection, multiple stings were tolerated with no reaction. In the second season, she had an anaphylactic reaction after a yellow jacket sting. Subsequently, there was a rising titer of serum yellow jacket and bee venom-specific IgE and positive skin-test reactions. In the third season, yellow jacket, hornet, and bee venom skin tests remained positive and serum IgE antibody titers remained elevated. Stings from all three insects were tolerated with no reaction. Throughout the 3-yr course, serum venom-specific IgG remained low and unchanged. The factors other than IgE-modulating clinical anaphylaxis, perhaps responsible for this clinical and immunologic dichotomy, are unknown. These observations add a further complication to the choice of patients for venom immunotherapy.