Martin D. Valentine

A controlled trial of immunotherapy in insect hypersensitivity.

Insect hypersensitivity is currently treated by immunization using whole-body extracts. We compared this regimen with immunotherapy using insect venoms or placebo in groups of 20 patients matched for history and sensitivity, as judged by venom skin test, histamine release and IgE antibody to venom. After six to 10 weeks of immunization, systemic reactions to stings occurred in seven of 12, seven of 11, and one of 18 patients treated with placebo, whole-body extract, and venom, respectively. Placebo and whole-body extract gave similar results and were significantly less effective than venom immunotherapy (P less than 0.01). The 14 patients with failure of treatment with whole-body extract and placebo were subsequently provided with venom immunotherapy; one reacted to a subsequent sting. We conclude that venom immunotherapy is clinically superior to therapy on whole-body extract or placebo.

The Value of Immunotherapy with Venom in Children with Allergy to Insect Stings

BACKGROUNDnThe treatment of patients allergic to insect stings with insect-venom injections has been shown to be 97 percent effective in reducing the risk of sting-induced anaphylaxis. However, the frequency of systemic reactions to subsequent stings in unimmunized adults with previous reactions is approximately 60 percent. To determine which factors, in addition to a history of reaction and evidence of venom-specific IgE antibody, predispose patients to future insect-sting reactions, we studied a venom-sensitive group of children who were deemed to be at relatively low risk for severe reactions; 28 percent of them received venom therapy.nnnMETHODSnWe studied 242 children, 2 through 16 years of age, each of whom had had a systemic allergic reaction, affecting only the skin, to an insect sting. Each child had a positive skin-test reaction to one or more of five hymenopteran venoms. Sixty-eight children received immunotherapy with insect venom and 174 did not; about half were randomly assigned to treatment groups, and the rest were assigned on the basis of the patients (or the parents) choice. The results of accidental stings during four years of observation were evaluated.nnnRESULTSnIn the treated group, 84 stings in 36 patients resulted in one systemic reaction (1.2 percent of stings). In contrast, 196 stings in 86 untreated children resulted in 18 systemic reactions (9.2 percent of stings, P less than 0.001). Sixteen of these 18 reactions were judged to be milder than the patients reaction to the first sting, 2 were similar in severity, and none were more severe.nnnCONCLUSIONSnThese data confirm that immunotherapy with insect venom prevents recurrences of systemic reactions after subsequent insect stings. Because of the surprisingly low rate of reactions among untreated children, we could not identify any characteristics that were predictive of repeat reactions. Since only 9.2 percent of stings in the untreated children led to a systemic reaction and since there was no progression to a more severe reaction, we conclude that venom immunotherapy is unnecessary for most children who are allergic to insect stings.

Insect allergy: the state of the art.

There has been significant recent progress in the diagnosis and treatment of patients with Hymenoptera sensitivity.‘-” Many problems remain, and, indeed, the introduction of new information has raised additional questions. Treatment is highly efficacious but expensive, of long duration, and has an unknown degree of long-term side effects. The question of whom to treat, therefore, becomes critical. With the commercial availability of venoms for immunotherapy, the practicing allergist will need to make a series of difficult decisions. With this in mind, it seems appropriate to present our clinical and laboratory experience during the last five years and to summarize our suggestions concerning the management of patients with an allergy to insect stings. Our recommendations are derived from experience with the evaluation of over 500 patients and the therapy, including inhospital sting, of over 300 adults and children. A degree of controversy persists in this field, and additional data must be gathered before a fully defined position can be established. We have tried to make what follows as precise a statement of what is and is not known as is currently possible. Whole body extract therapy In the first volume of the

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 microgram/ml) than in the successes (7.3 +/- 1.1 microgram/ml) (p less than 0.01). When the failures were successfully treated, their mean IgG level (6.1 +/- 1.3 microgram/ml) was significantly greater than that associated with treatment failure (p less than 0.025). Patients with an IgG antibody level above 5.0 microgram/ml were significantly more likely to be fully protected (p less than 0.02). Those whose IgG levels were less than 5 microgram/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.

Regimens of Hymenoptera Venom Immunotherapy

We studied 64 sting-allergic patients treated with one of three regimens of insect-venom immunotherapy: slow, rush, or a step-function regimen. All regimens had a top dose of 100 micrograms and a similar cumulative dose. Efficacy was 100% in all regimens. Fifty percent of the patients had at least one large local reaction at a rate of 9.6 reactions/100 injections. Sixteen percent had systemic symptoms at 1.6 reactions/100 injections. Reaction rates did not differ among the groups, but the slow regimen involved twice as many injections as the rush regimen, and thus caused twice the number of reactions. The rush regimen caused a greater and more rapid rise in anti-venom IgG than did the slow regimen, with no difference in IgE levels. We conclude that although equally effective, the rush regimen of venom immunotherapy is associated with a greater immune response and fewer adverse reactions that the slow regimen.

Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms

SKin testing was done on 30 patients with a history of anaphylactic reactions after a Hymenoptera sting and on 30 control subjects. The patients all had positive basophilhistamine release to one or more venoms on challenge with the specific venoms used for skin testing (honey bee, yellow jacket, white-faced hornet, yellow hornet, and Polistes). At 0.1 mug of venom/ml and at 1.0 mug of venom/ml, 75% and 100%, respectively, of the sensitive patients had a positive skin test. There was a significant (P less than 0.001) correlation between skin test and histamine release results. Of the 150 skin tests in control patients, only 1 was positive. Venom skin tests provide, for the first time, a simple, readily available technique to accurately diagnose allergy to stinging insects.

Discontinuing venom immunotherapy: Outcome after five years

BACKGROUNDnThe clinical and immunologic consequences of discontinuing venom immunotherapy are not well-defined. To determine which patients can safely stop treatment, we accepted all volunteers who had completed at least 5 years of maintenance venom immunotherapy regardless of the severity of the historical sting reaction, the persistence of venom skin test sensitivity, or any other variable.nnnMETHODSnSting challenge was performed every 1 to 2 years after therapy was stopped; and venom-specific skin tests were performed, and IgE antibody levels were measured.nnnRESULTSnSystemic symptoms occurred after challenge in eight of 270 stings (3%), in seven of 74 patients (10%); only two reactions were clinically significant. Venom skin test results became negative in 28% after 5 years of venom immunotherapy (at the time of discontinuation) and were negative in 56% to 67% of patients after 2 to 4 years without venom immunotherapy. There was a parallel decrease in the venom-specific IgE antibody levels. Challenge stings did not prevent the progressive decline in sensitivity, nor did they increase the risk of sting reaction even after two sequential stings 1 month apart.nnnCONCLUSIONSnVenom immunotherapy can be safely discontinued after 5 years of maintenance therapy in virtually all patients, with the possible exception of those in whom the level of venom sensitivity has not declined during therapy. Venom sensitivity decreases with time even after venom therapy is stopped. Insect stings do not cause re-sensitization, and there was no increased risk from sequential stings. There appears to be a late-onset, non-IgG-mediated mechanism for long-term suppression of allergic sensitivity by prolonged high-dose venom immunotherapy.

Dose dependence of Hymenoptera venom immunotherapy

The clinical and immunologic efficacy of venom immunotherapy up to 50 micrograms 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-micrograms 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-micrograms maintenance doses. The venom-specific IgG antibody response to the 50-micrograms dose reached a level significantly lower than observed with 100 micrograms 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 micrograms of each venom than at a dose of 50 micrograms.

A Case for Venom Treatment in Anaphylactic Sensitivity to Hymenoptera Sting

Abstract In a child of a beekeeping family anaphylaxis developed after a honey-bee sting. He was treated with the conventional therapy, whole-(insect)-body extracts, for nine months. A second sting caused anaphylaxis again. Since the patients family history included a sister who had died in similar circumstances, he was immunized with 1.4 mg of honey-bee venom over a two-month period; the last two doses were 100 μg (≅ two bee stings). His sensitivity to venom, assessed by basophil histamine release, decreased, and his blocking (IgG) antibody level increased 300 times over that after immunization with whole-body extract. After venom immunization he tolerated a honey-bee sting without reaction. The case and a review of pertinent data suggest that venom immunization may be the treatment of choice for hymenoptera sensitivity. (N Engl J Med 290:1223–1227, 1974)

Allergy to insect stings. II. Phospholipase A: the major allergen in honeybee venom.

In order to determine the proteins of major allergenic importance in honeybee venom (Apis mellifera) it was chromatographed on G-50 Sephadex. The four major protein peaks eluted were identified as hyaluronidase, phospholipase, melittin, and apamin. Testing these preparations on the leukocytes of 6 honeybee-sensitive patients, with the in vitro method of histamine release, revealed that all individuals were most sensitive to phospholipase A. IgE antibodies against phospholipase A (RAST) were found in the sera of honeybee-sensitive patients and IgG antibodies to this venom component were found in the sera from beekeepers and venom-treated patients. Melittin appeared to be allergenic in several patients, but the results were variable and were possibly due to contamination with phospholipase. All patients were insensitive to the hyaluronidase and apamin preparations. We conclude that phospholipase A is the major allergen of honeybee venom and, since this protein is readily available, it should be useful for diagnostic and therapeutic studies as well as for the standardization of materials used in the management of honeybee-sensitive patients.