Decrease of IgE-dependent platelet activation in Hymenoptera hypersensitivity after specific rush desensitization.

A receptor for the Fc fragment of IgE on human platelets has been recently described, which mediated an IgE-dependent activation in the presence of specific allergen. We investigated the allergen-induced activation of platelets from patients with Hymenoptera hypersensitivity before and after specific rush desensitization. Nineteen patients with a history of anaphylactic reactions were included (15 sensitive to yellow-jacket and four to honey-bee venom), fourteen/nineteen having experienced severe life-threatening systemic reactions and 5/19 large local reactions. All showed positive skin tests and high values of specific IgE. By comparison to the baseline results obtained before desensitization, a significant decrease of platelet activation (76.8% inhibition) after rush desensitization was observed. In the case of two polysensitized patients, after Hymenoptera venom desensitization alone, platelets not only lost their reactivity to venom but also towards the other allergen. This modulation of the IgE-dependent platelet reactivity during desensitization offers therefore a new approach for the study of allergen-induced desensitization.     

Prospective observations on stopping prolonged venom immunotherapy

After a decade spent establishing the safety, efficacy, and optimal techniques for venom immunotherapy, we have begun a series of studies to determine how long venom immunotherapy must be continued. In retrospective surveys, patients who had stopped venom immunotherapy after 1 to 2 years had a substantial risk (25%) of systemic sting reactions, but this was less than 50% of the risk in untreated patients. In this first prospective study, 30 patients elected to stop venom immunotherapy after at least 5 years of therapy. Skin test sensitivity had decreased significantly during therapy in 18/30 patients but remained clearly positive in 23/30 (seven patients became equivocal or negative). Serum venom-specific IgE antibodies were at the lower limit of detection (1 ng/ml) in 11/30 patients. After stopping treatment, the mean serum venom-specific IgG antibody level declined from 5.5 +/- 0.6 micrograms/ml to 2.4 +/- 0.3 micrograms/ml by 9 months, which is the same as the mean venom IgG in untreated patients. After 12 months without therapy, live sting challenge caused no systemic reaction in 29 patients. The mean venom IgG level 1 month after the sting had risen significantly to 4.1 +/- 0.5 micrograms/ml, but there was no significant increase of venom IgE. These results suggest that prolonged venom immunotherapy leads to isotype-specific suppression of the venom IgE antibody response and may provide persistent clinical protection by mechanisms other than IgG blocking antibodies. The observations are to be interpreted very cautiously. Further investigations are needed to extend these observations in additional patients and for longer periods of time, and to examine possible mechanisms for this apparent loss of clinical reactivity.     

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.     

Diagnostic value of the skin-prick test and RAST assay in insect sting allergy

The results of skin-prick tests to four concentrations of venom (0.1, 1, 10 and 1000 μg/ml) carried out on two occasions were analysed in relation to the history of adverse reactions to stings and to the level of venom-specific IgE antibody in serum, in forty-two subjects allergic to insect stings (sixteen to bee and twenty-six to wasp). Fifty control subjects (some of whom had never been stung by bee or wasp) with no history of adverse reaction to stings were also studied. No subject gave a positive skin-test reaction to 0.1 μg/ml, and small numbers reacted to either 1 or 10 μg/ml. The lowest concentration of venom to which most subjects had a positive skin test was 100 μg/ml. Our data suggest that in wasp-allergic patients a positive skin test to 100 μg/ml is normally significant (reflecting the presence of specific IgE), whereas in bee-allergic patients a skin test reaction to 100 μg/ml is usually non-specific for the following reasons. (i) In the allergic patients when skin tests were repeated, a reaction to 100 μg/ml bee venom often became negative (in six of eight), whereas for wasp venom the reaction became more positive (at 10 or 1 μg/ml) in seven of eight patients. Whilst this might reflect lack of reproducibility, the consistent direction of change for either bee or wasp venom suggests responses to this concentration of these venoms may have different interpretations. (ii) In bee-allergic patients, where positive skin tests to 100 μg/ml wasp venom were found they were repeatable in all patients, and occurred only in patients who had been stung by a wasp. In wasp-allergic patients, skin test reactions to 100 μg/ml bee venom were not reproducible between studies in any patient and often occurred in subjects never stung by a bee. (iii) A better correlation between skin test and RAST occurred for wasp venom when a skin-test reaction to 100 μg/ml was included as a positive (rather than reactions to 1 or 10 μg/ml only). For bee venom the correlation did not improve when skin-test reactions to 100 μg/ml were included. (iv) In the control group, skin-test reactions to 100 μg/ml bee venom were often false positives (seven of eight had never been stung by a bee). Four out of fifty controls reacted to wasp venom 100 μg/ml, but three of these had received a wasp sting. These findings suggest that in routine clinical practice skin tests should be carried out over the range 1–10 μg/ml in bee-allergic subjects but in wasp-allergic patients 100 μg/ml should also be included. Extracts of 0.1 μg/ml need not be used.     

Reduction of interference by specific IgG with a modified microtiter solid-phase radioimmunoassay to measure honeybee venom IgE

By means of monoclonal mouse anti-human IgE antibody, the microtiter solid-phase radioimmunoassay (MSPRIA) was modified to measure honeybee venom (HBV) IgE. HBV IgG was measured by MSPRIA(G) using affinity column purified goat anti-human IgG antibody and correlated with results obtained with staphylococcal protein A-SPRIA. Nonlinear specific IgE dilution curves were associated with high HBV IgG content. By serial transfer and assay of the supernatant, the interference of IgE by specific IgG could be reduced. The degree of interference was correlated with the specific IgG content. The principle of serial supernatant transfer and assay was applied to the standardization of reference HBV IgE serum, and the quantitation of HBV IgE contents in patients and controls. HBV IgE levels in patients allergic to honeybee stings correlated with the skin-test endpoint titrations. While 75% of the allergic patients were skin-test positive, 83% of them were IgE positive by the MSPRIA and 67% were IgE positive by the RAST.     

Allergic reactivity and socio-economic level in a tropical environment

As some factors associated with the tropical environment can modify the expression of atopic disease, various indicators of allergic reactivity were compared between allergic and non-allergic subjects of different socio-economic level in Caracas, Venezuela (Lat. 10°N). The socio-economic levels considered were high (HSEL), medium-high (MSEL) or low (LSEL). As generally found in temperature climates, in the HSEL the total serum IgE levels of allergic patients were significantly greater than those of nonallergic individuals (geometric means of 274 vs 126 IU/ml, respectively), as were also the specific serum IgE antibody levels (55.6 vs 23.8% positive, respectively, for house dust). These results correlated closely with the skin-test reactivity of these subjects (60.3 vs 17.5% positive for house dust). In this group, the degree of intestinal helminthic infection was low (5.6% positive for Ascaris). In contrast, for the MSEL where the degree of parasitic infection was higher (13.0%), the total serum IgE levels were elevated in both allergic and non-allergic subjects (602 vs 363 IU/ml). Similarly, positivity for specific IgE antibody was high, and comparable between allergies and non-allergies of this group (61.5 vs 54.2%), as was also the case for skin-test reactivity (71.9 vs 60.4%). In the LSEL, parasitic infection was prevalent (47.6%), and the total serum IgE levels were markedly elevated, with little difference occurring between allergic and non-allergic individuals (2269 vs 1981 IU/ml). The positivity for specific IgE antibody was high, and effectively independent of the allergic state (75.6 vs 53.7%), but in contrast the skin test reactivity was relatively low (22.0 vs 9.8%). The lack of correlation between skin test and specific IgE results in this group appeared to have     

IgE, IgG, IgG1 and IgG4 patterns in yellow jacket allergic patients during immunotherapy with a venom depot extract

Using immunoblot studies, detailed antibody patterns were performed with the sera of 10 yellow jacket allergic patients undergoing specific immunotherapy with a yellow jacket venom SQ-depot extract (ALK, Denmark). Five males and five females (age range 10-65, mean 48 years) were investigated. All patients had a history of systemic reactions after an insect sting and a positive skin-prick test at a dose of at least 100 micrograms/ml yellow jacket venom. Yellow jacket venom (ALK) was separated on a 7.5-20% SDS-PAGE, transferred to nitrocellulose (NC), and then the NC-strips were incubated with the patients' sera. For detection of IgE, IgG, IgG1 and IgG4, an alkaline phosphatase linked 2nd antibody was used. Prior to immunotherapy, a strong IgE binding was detected at 25 kD in nine of 10 patients, representing Antigen-5 (Ag-5) as major allergen. Reactivity to this antigen was also present with the other immunoglobulin classes, although not as marked. In addition, a second frequent IgG and IgG1-binding band was seen at 35 kD (phospholipase A). Only weak or no binding to this band was found with IgE and IgG4. Binding to hyaluronidase (43 kD) was seen only in three cases. During immunotherapy, a significant increase in IgG and particularly IgG4 staining was found with Ag-5, whereas hyaluronidase induces mainly an IgG1 response and phospholipase A showed only a weak IgG response. In addition, the formation of new IgG4 binding to proteins in the region of about 70-90 kD was found in most patients. The dose necessary for the induction of this antibody formation was greater than or equal to 150.00 SQ yellow jacket venom.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antibodies to purified bee venom proteins and peptides. II. A detailed study of changes in IgE and IgG antibodies to individual bee venom antigens

Antibodies to individual bee venom antigens were studied in detail in nine bee sting-allergic patients who received venom immunotherapy without side effects, in two patients who failed to reach maintenance, and in two whose sensitivity returned. The study was confined to patients who had IgE antibodies to at least one of four purified bee venom antigens at the start of treatment. IgE and IgG antibodies to phospholipase A2 (PLA2), hyaluronidase (HYAL), and acid phosphatase (ACID P) and IgE antibodies to melittin (MEL) were measured, and changes in the antibody levels were followed during bee venom immunotherapy. Two contrasting patterns of antibody response were seen in the nine successfully treated patients. In five patients there was a rise in serum IgG antibodies to the same antigens as the IgE antibodies. In two patients' serum IgE antibody to HYAL or ACID P fell without a marked IgG antibody response to these antigens, although high levels of IgG antibody to PLA2 were present in both. Although the first pattern is consistent with a "blocking" role for IgG antibody, clearly the second is not. Not all patients can be conveniently divided into these two categories, and two patients did not show any significant change in either IgG or IgE antibody but were nevertheless able to tolerate the maintenance dose of 100 micrograms of venom. Two patients who failed to reach the maintenance dose of 100 micrograms because of their allergic reactions to the injections of venom were distinguished by (1) very high serum IgE antibody and (2) a low ratio of IgG/IgE antibody. Passive immunization with IgG antibody from a hyperimmune beekeeper was, however, protective in these patients, although it did not raise their overall serum IgG antibody level very much. We are unable to explain either the failure of conventional therapy or the beneficial effect of passive immunization in these two patients. Two bee sting--allergic beekeepers lost their sensitivity to stings, but later, when their sera contained IgE antibody to another bee venom antigen, they reacted to stings and inhalation of beehive dander. These data suggest that either falling IgE antibody or IgG- "blocking" antibody could be responsible for providing clinical protection to bee venom--allergic subjects. Renewed clinical sensitivity was observed when the IgE response was modulated, with patients making IgE antibody first to one antigen and then to another.     

Human immunoglobulin E and immunoglobulin G antibody responses to the “minor” ragweed allergen Ra3: Correlation with skin tests and comparison with other allergens

We report here the use of an antigen-binding assay to measure serum IgE and IgG binding activity (BA) for the “minor” ragweed antigen, Ra3. These studies were carried out in ragweed-allergic individuals, many of whom had been skin tested with Ra3 as well as with the “major” ragweed allergen, antigen E (AgE). IgE BA for Ra3 showed a weak quantitative correlation with skin-test sensitivity to Ra3. More strikingly, there was a threshold of skin sensitivity (<10^?3 μg/ml) above which serum IgE BA was likely to be detectable. Serum IgG BA for Ra3 measured in parallel with IgE BA was found in all sera that showed detectable IgE BA for Ra3. By contrast, $\text{11}\text{13}$ ragweed-allergic individuals who were skin-test negative for Ra3 showed no detectable IgG BA for Ra3. These results support the view that the known genetic controls over Ra3 sensitivity control IgG antibody as well as IgE antibody responses. Individuals receiving injections of ragweed extract showed increases in IgG BA for Ra3 following therapy. Among nine persons who had no IgG BA for Ra3 before treatment, four out of nine developed a low degree of IgG BA for Ra3. However, the patients who developed IgG BA did not develop detectable IgE BA for Ra3.     

Lymphocyte-mediated inhibition of platelet cytotoxic functions during Hymenoptera venom desensitization: characterization of a suppressive lymphokine

Recently, it has been shown that platelets, through a receptor for the Fc fragment of IgE, could be specially triggered by venom allergens in hypersensitivity to hymenoptera, generating cytocidal mediators toward Schistosoma mansoni larvae, and oxygen metabolites measured by chemiluminescence. After rush immunotherapy, a depressed platelet response was demonstrated to be associated with the production of lymphokine(s). Here we report the characterization of a factor present in supernatants of antigen-stimulated T cells from patients after hymenoptera venom desensitization which is able to inhibit platelet cytotoxic functions in a dose-dependent manner. The optimal inhibition was observed with supernatants obtained after T lymphocyte stimulated with 10(-5) micrograms venom allergen/ml. Once specifically produced the platelet-suppressive effect of lymphocyte supernatants was not antigen specific. The producing T cell subpopulation was identified as CD8+. This lymphokine had an approximate molecular mass of 25 kDa and a pI of 4.8. It was heat and acid stable and sensitive to trypsin and proteinase K but not to neuraminidase. This platelet inhibitory activity was absorbed by platelet membrane suggesting its binding to a receptor. These properties were very similar to a previously described platelet activity suppressive lymphokine, suggesting the participation of this lymphokine in the mechanisms of rush desensitization.     

Mechanism of activation of human basophils by Staphylococcus aureus Cowan 1

We investigated the capacity of Staphylococcus aureus Cowan 1 and S. aureus Wood 46 to induce histamine release from human basophils in vitro. S. aureus Cowan 1 (10(5) to 10(7)/ml), which synthesizes protein A (Staph A), stimulated the release of histamine from basophils, whereas S. aureus Wood 46 (10(5) to 2 X 10(7)/ml), which does not synthesize Staph A, did not induce histamine secretion. Soluble Staph A (10(-3) to 10 micrograms/ml), but not staphylococcal enterotoxin A, induced histamine secretion from human basophils. Staph A binds through its classical site to the Fc region of human immunoglobulin G (IgG) and through its alternative site to the Fab portion of the different human immunoglobulins. Hyperiodination of Staph A, which destroys over 90% of the original Fc reactivity without altering the Fab-binding site, did not alter the ability of the protein to induce histamine release. The stimulating effect of Staph A was dose dependently inhibited by preincubation with human polyclonal IgG (0.3 to 100 micrograms/ml) and a human monoclonal IgM (0.3 to 100 micrograms/ml) which have F(ab')-Staph A reactivity. In contrast, rabbit IgG, which possesses only Fc-Staph A reactivity, and a Staph A-unreactive human monoclonal IgM did not inhibit Staph A activity. Similar results were obtained with intact S. aureus Cowan 1. Preincubation with either Staph A or anti-IgE (rabbit anti-Fc epsilon) resulted in complete desensitization to a subsequent challenge with the homologous stimulus. Staph A and anti-IgE induced partial cross-densensitization to the heterologous stimulus. Cells preincubated with anti-IgG (rabbit anti-Fc gamma) lost a small but significant part of their ability to release with Staph A but did not lose their response to anti-IgE. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released histamine in response to anti-IgE and Staph A. When basophils from which IgE had been dissociated were incubated with human polyclonal IgE, they regained their ability to induce histamine in response to Staph A and anti-IgE. In contrast, two monoclonal IgEs which do not bind to Staph A did not restore the basophil responsiveness to Staph A. Furthermore, there was complete cross-desensitization between soluble Staph A and S. aureus Cowan 1, while cells desensitized to S. aureus Wood 46 released normally with Staph A and S. aureus Cowan 1.(ABSTRACT TRUNCATED AT 400 WORDS)     

A multicenter study on skin-test reactivity of human volunteers to venom as compared with whole body Hymenoptera antigens

Twenty-four control and 104 stinging insect—allergic patients were tested in this multicenter study, which compared the utility of individual venom and whole body extract (WBE) preparations for diagnosis. This study indicates that venom skin testing is more specific and more reliable than is testing with WBE. There was a high rate of WBE skin-test reactivity among controls. False-positive skin testing with venom was not a problem at concentrations of 1 μg/ml or less. Only one mild and easily treated adverse reaction occurred in this study.     

Clinical and immunologic observations in patients who stop venom immunotherapy

It is currently recommended that venom immunotherapy (VIT) be continued as long as the sensitivity persists (indicated by positive venom skin tests or RAST). In this pilot study, we performed a retrospective survey of the clinical and immunologic effects of stopping VIT. The 82 patients studied had received maintenance VIT for a mean of 14 months and had stopped VIT a mean of 43 months before evaluation. Subsequent "field" stings in 28 patients caused systemic reactions in six cases (22%), which is significantly higher than the 1% to 3% systemic reaction rate in patients who remain on maintenance VIT. The 22% reaction rate is a minimal estimate caused by loss of venom sensitivity in some patients and residual venom-specific IgG antibody levels in others. Reevaluation of venom skin tests and IgG levels was possible in 43 patients. A tenfold decline from before VIT skin test results was observed in 27 patients (63%). Skin tests remained clearly positive in 32/43 (74%), became weakly positive in 9/43 (21%), and 2/43 (5%) became negative. The IgG level declined from typical maintenance levels before stopping VIT (mean 7.2 +/- 1.2 micrograms/ml) to levels typical of untreated patients at the time of retesting (mean 1.95 +/- 0.3 micrograms/ml). Despite the marked fall of IgG antibody, one third of the patients still had levels in the average range observed in patients receiving maintenance VIT. We conclude that there is a substantial risk of anaphylactic sting reaction if VIT is stopped while venom sensitivity persists.     

Serial immunological investigations in a patient who had a life-threatening reaction to intravenous protamine

Reactions to intravenous protamine include rash, urticaria, bronchospasm, hypotension, and/or pulmonary artery pressure elevation. We have previously shown that in diabetic patients receiving daily protamine-insulin injections, the presence of anti-protamine IgE or IgG antibodies are significant risk factors for acute, life-threatening reactions when protamine is given intravenously. To study protamine reactions further, we measured serum anti-protamine IgE and IgG antibody levels, in-vitro basophil histamine release and intracutaneous skin testing to protamine serially in an NPH-insulin dependent diabetic who had a severe, protracted anaphylactic reaction to protamine. At the time of his protamine reaction, his serum contained 8.5 ng/ml of anti-protamine IgE and 1.3 micrograms/ml of anti-protamine IgG antibody. One month following the reaction both anti-protamine IgE and IgG increased to 16 ng/ml (twofold rise) and 90.5 micrograms/ml (70-fold rise), respectively. With time, both anti-protamine IgE and IgG antibody declined. Serial intradermal skin tests using protamine sulphate did not discriminate between the protamine reactor and nine normal control subjects who had no prior exposure nor any demonstrable serum IgE antibody to protamine. In-vitro basophil histamine release to protamine sulphate was inconclusive in discriminating between the protamine reactor and normal control subjects. We postulate that protamine may be an incomplete or univalent antigen that must first combine with a tissue macromolecule or possibly heparin to become a complete multivalent antigen capable of eliciting IgE antibody-dependent mediator release.     

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.     

Systemic reactions during maintenance immunotherapy with honey bee venom

Immunotherapy with hymenoptera venoms is safe and effective in most patients but treatment failures have been reported. Five patients experienced systemic symptoms of anaphylaxis when they were in maintenance immunotherapy with honey bee venom. In one case, the patient presented a severe life-threatening reaction when stung by a honey bee. Three others had the development of new clinical sensitivity suggesting a re-sensitization. This occurred in the fifth patient after a severe viral infection. By means of a rush protocol and monthly doses of 200 to 400 micrograms of honey bee venom, the patients were subsequently protected efficiently. In most cases these reactions might have been predicted since patients experienced large local reactions prior to the systemic reactions when allergens were injected. Further, in four cases there was an increased skin test reactivity or raised serum honey bee venom IgE levels or both. In all patients, the levels of serum honey bee venom IgG was under 200 U/mL (IgG Pharmacia RAST).     

Effect of specific IgG on IgE-induced systemic anaphylaxis in the rabbit

Immunization of rabbits as neonates and periodically thereafter has been shown to induce the long-term preferential production of specific IgE antibodies. Specific IgG antibodies are not detected in the majority (greater than 70%) of rabbits when classical immunological detection techniques are used, including heterologous PCA in guinea-pig skin. Nevertheless, in this study we demonstrate that all rabbits neonatally immunized to the antigen horseradish peroxidase (HRP) do produce low levels of specific IgG antibody detectable by an ELISA technique. Serum levels of anti-HRP IgG were found to be log normally distributed, with a geometric mean for the heterologous PCA-negative sera of 31.6 X/divided by 2.69 micrograms/ml. Serum anti-HRP IgE levels (log2 homologous PCA titres) are bimodally distributed. Specific IgG and IgE levels in individual rabbits have a significant direct relationship. Six heterologous PCA-negative and seven heterologous PCA-positive rabbits were challenged intravenously with HRP. All of the respiratory and circulatory alterations typical of IgE anaphylaxis occurred in every challenged rabbit. Regression analysis of percentage changes in the physiological variables vs log specific IgE level indicated that none of the changes was either directly or inversely related to the specific IgG levels. Also the mean changes of the heterologous PCA-positive vs negative rabbits did not differ significantly. Thus, we could find no evidence for either a blocking or enhancing effect of the specific IgG antibodies (range 10-529 micrograms/ml serum) on the IgE-induced anaphylactic reaction.     

Late onset reactions following venom immunotherapy and venom skin tests

This report describes patients who had late onset reactions following venom immunotherapy and venom skin tests. Six adult patients had symptoms of fatigue, malaise, fever, headache, and joint ache, starting four to six hours after venom immunotherapy and lasting up to four days. Two of the patients had prolonged reactions at or adjacent to the skin test sites. All of these patients had a history of venom anaphylaxis; four had severe cardiovascular symptoms. All received yellow jacket venom immunotherapy and four honeybee venom immunotherapy. In four patients, the reactions occurred following small venom doses, 0.1 to 2 micrograms. Two patients reacted after maintenance doses of 50 micrograms. There was no relationship to the serum IgE or IgG antibody titers. All but one patient had serum venom-specific IgE but the titers covered a wide range. Serum venom-specific IgG was present in four patients. There was no response in lymphocyte culture to bee venom stimulation in two patients. Two of these patients stopped venom immunotherapy; one had reached the maintenance dose. In three patients, prophylactic parenteral steroids have ameliorated the reactions. After a temporary dose reduction, the sixth patient is now asymptomatic. A seventh patient developed asthma, 12 hours following a maintenance dose of 50 micrograms of yellow jacket venom. Concomitant steroid administration has effectively prevented the reaction. Another patient, a 6-year-old boy, developed fever, edema of the face and lips, erythema of the leg, and a large, tender right inguinal node eight hours following venom skin tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical relevance of the venom-specific immunoglobulin G antibody level during immunotherapy

Parameters associated with successful venom immunotherapy in insect allergy were sought by comparison of treatment failures with successes. Half-dose treatment was completely protective in 32 patients (successes) but was only partially effective in eight (failures). The outcome of treatment was not related to the severity of pretreatment sting reactions, to the degree of skin-test sensitivity, to an atopic personal history, or to age or gender. The mean yellow jacket venom-specific IgG antibody level (by the Staph-A solid-phase radioimmunoassay) was significantly less in the failures (3.9 ± 0.6 μg/ml) than in the successes (7.3 ± 1.1 μg/ml) (p < 0.01). When the failures were successfully treated, their mean IgG level (6.1 ± 1.3 μg/ml) was significantly greater than that associated with treatment failure (p < 0.025). Patients with an IgG antibody level above 5.0 μg/ml were significantly more likely to be fully protected (p < 0.02). Those whose IgG levels were less than 5 μg/ml had a risk of reaction similar to that in untreated patients. We conclude that early in the maintenance phase of low-dose venom immunotherapy, the risk of a reaction to a challenge sting is significantly greater for those patients with low levels of venom-specific IgG antibodies.     

Assessment of venom-specific IgG antibody in patients treated for hymenoptera allergy

The IgG antibody (Ab) response achieved with specific venom immunotherapy was explored in 32 patients with Hymenoptera hypersensitivity. Venom-specific IgG Ab was quantitated before and after 1 year of immunotherapy using two solid phase radioimmunoassay (SPRIA) methods. An agarose-based test using 125I-Staphylococcus aureus Protein A (SPRIA) was used to determine specific IgG for five Hymenoptera species: yellow jacket (YJ), honeybee (HB), yellow-faced hornet (YH), white-faced hornet (WFH), and Polistes (POL). A cellulose disk test using 125I-anti-IgG (IgG RAST) was available only for YJ and HB venoms. Acceptable agreement (90% concordance) was observed with IgG anti-HB levels measured in the two assays. For the YJ-IgG, however, 17/69 (25%) of sera positive in the SPRIA were negative in the IgG RAST, whereas the converse was not observed. This result suggests that the IgG RAST is insufficiently sensitive to detect YJ-IgG responses in all patients on maintenance level immunotherapy. Using the Protein A SPRIA, there was excellent agreement between the venom used for immunotherapy and the specificity of the IgG Ab response. In 31 patients treated with a total of 90 venom species, 90/90 venom IgG levels were increased or maintained at high pretreatment levels in response to immunotherapy. In the same patients venom IgG levels obtained for venom species not included in therapy were undetectable or declined in 55/60 cases; in 4 cases treatment with YJ venom stimulated a WFH and/or YH IgG response, the remaining case, YJ venom stimulated a small rise in POL IgG. These apparent discrepancies can be explained by variable cross-reactivity among vespid and POL venoms. Among 32 patients with a combined total of 87 positive venom skin tests, 1 year of specific immunotherapy resulted in greater than 5 micrograms/ml of venom-specific IgG in 61 instances. In 25 instances, the level of venom IgG was detectable but less than 5 micrograms/ml, and in 1 case venom IgG could not be detected. Based on recent analyses by Golden et al., some or all of these latter 26 cases may represent suboptimal therapy despite a standard immunotherapy regimen. We conclude that venom IgG measurements can provide a specific and quantitative assessment of the immunologic response to venom therapy, and that such assessment may be clinically useful in detecting instances of suboptimal immunotherapy.