Antigen-induced release of slow reacting substance of anaphylaxis (SRS-A rat) in rats prepared with homologous antibody.

The polymorphonuclear leukocyte appears to be an essential cellular prerequisite for the antigen-induced release of SRS-A(rat) in the peritoneal cavity of rats prepared with homologous, hyperimmune antisera. Depletion of PMN leukocytes is associated with a marked suppression of SRS-A(rat) release, whereas depletion of circulating lymphocytes or peritoneal mast cells does not influence the antigen-induced release of SRS-A(rat). A local increase in the number of PMN leukocytes produced by the induction of a peritoneal exudate was associated with an enhanced release of SRS-A(rat). A distinct difference in the cellular requirements for the antigen-induced release of histamine and SRS-A(rat) in the rat was observed. Homocytotropic antibody-mediated histamine release could be achieved in leukopenic rats but not in mast cell-depleted animals. Conversely, SRS-A(rat) release was suppressed in leukopenic rats but was unaffected by mast cell depletion. Diethylcarbamazine inhibited the antigen-induced release of SRS-A(rat) following preparation with homologous, hyperimmune antisera but did not interfere with homocytotropic antibody-mediated histamine release. In preventing SRS-A(rat) release, diethylcarbamazine did not interfere with antigen-antibody interaction since desensitization of tissues was possible in the presence of this inhibitor. This observation is consistent with the view that diethylcarbamazine inhibits the reaction sequence leading to the formation and release of SRS-A(rat) at some step subsequent to antigen-antibody interaction. These studies support the view that the immunologic pathways leading to the release of SRS-A(rat) and histamine in the rat are distinctly different in terms of the immunoglobulins involved, the cellular prerequisites, and the effective pharmacologic inhibitors.

Release of slow-reacting substance of anaphylaxis in the rat: polymorphonuclear leukocyte.

The antigen-induced release of slow-reacting substance of anaphylaxis was studied in rats previously treated with different biological and pharmacological agents to deplete these animals of specific cellular elements. The polymorphonuclear leukocyte appears necessary as a crucial cell type for optimum release of the slow-reacting substance of anaphylaxis, whereas the mast cell and lymphocyte are not required.

Physiologic manifestations of human anaphylaxis.

In the course of a controlled study to evaluate different forms of immunotherapy for subjects with insect-sting hypersensitivity, we observed 11 subjects who had systemic cutaneous urticarial reactions and 3 subjects who experienced systemic anaphylaxis. With the exception of tachycardia, there were no cardiopulmonary changes in the subjects with urticaria, whereas the major manifestation of anaphylactic shock in the other three subjects was severe hypotension that was probably secondary to peripheral vasodilation. Significant abnormalities in gas exchange developed in two subjects. In one, bronchospasm precipitated a respiratory arrest followed by endotracheal intubation with mechanical ventilation. Although plasma histamine levels were not related to the development of cutaneous reactions, the plasma histamine levels correlated with the severity and duration of the cardiopulmonary changes observed during anaphylactic shock. The two subjects with the most severe shock showed evidence of intravascular coagulation characterized by a diminution of Factor V, Factor VIII, fibrinogen, and high molecular weight kininogen, as well as changes in components of the complement system. Standard therapy with epinephrine and fluids, usually recommended for the treatment of systemic anaphylaxis, did not immediately reverse either the hemodynamic or the respiratory abnormalities in the two subjects with the most severe anaphylactic shock. Hemodynamic recovery was gradual and did not seem directly related to any specific therapeutic intervention.

Insect venom allergy: diagnosis and treatment.

Allergy to insect venom is IgE mediated. Untreated, it occasionally terminates fatally and often causes temporary illness. Medical intervention with venom immunotherapy in patients with prior systemic reactions presents reactions to stings by inducing IgG-antibody formation, although in some groups of patients this results in little real benefit. Emergency self-treatment kits (Epi-Pen and Epi-Pen Jr., Center Laboratories, Port Washington, N.Y.; Ana Kit, Hollister-Stier, Spokane, Wash.), if promptly and intelligently used, may reverse most moderate sting reactions. Some severe reactions require aggressive therapy. Until better treatment criteria are available, the most certain way of reducing the risk of systemic reactions to stings is with venom immunotherapy.

Allergens of hymenopteran venoms.

Venoms of the Hymenoptera are mixtures of several antigens with nonimmunogenic small peptides and vasoactive amines. Limited local toxicity occurs with stings; systemic reactions to venoms are mediated by IgE antibodies and can be prevented by immunization with the appropriate venom. Skin testing with venoms detects the sensitized state, and a positive test predicts a 50 to 60% risk of an allergic response to a future sting. Because considerable crossreactivity exists between vespid venom allergens, choice of correct venom(s) for immunotherapy will not always be indicated by skin-testing with whole, unfractionated venom. Further efforts at skin testing with individual venom antigens may help to resolve problems regarding choice of venoms for immunotherapy.

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.

Immediate (IgE-mediated) skin testing in the diagnosis of allergic disease.

Immediate (IgE-mediated) skin tests are widely used in the diagnosis of allergic diseases. Skin tests correlate well with more specialized studies (RAST, histamine release and provocation tests) in the diagnosis of allergic disease. Lack of standardization and quantitation of biologic potency of allergens make critical comparison of skin test results impossible. A survey of practicing allergists yielded widely divergent opinions concerning the effect of anti-allergic drugs on skin tests. The results of published studies indicate that only antihistamines cause significant depression of skin reactivity. Therefore, therapy for asthma may be continued while diagnostic skin testing is in progress, avoiding the possible morbidity associated with discontinuing pharmacologic therapy.

Allergy to insect stings. IV. Diagnosis by radioallergosorbent test (R.A.S.T.).

Radioallergosorbent tests (RAST(s)) have been developed and assessed for the diagnosis of insect hypersensitivity by using a purified allergen from honeybee venom, phospholipase A, and crude yellow jacket venom. Sera from 193 patients positive both by history and skin test to one of these insects were compared with various groups of control sera. Eighty percent of sera from skin test-positive patients were RAST positive; positive RAST were found in 16% of sera tested from skin test-negative patients. A highly positive RAST correlates well with a positive skin test and clinical sensitivity, but serum IgE is not measurable in many patients with mast cell or basophil bound antibody. Since biologically important reactions of antigen with IgE require that the antibody be cell bound, skin testing would be preferred to RAST if one were limited to a single test for the diagnosis of insect allergy.

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.

Prolonged maintenance interval in hymenoptera venom immunotherapy.

To decrease the cost, inconvenience, and potential side effects of venom immunotherapy we tested whether the interval between the maintenance injections can be increased. In 30 patients who had been given the standard therapy regimen and who had been sting-challenged after 1 and 2 yr of monthly maintenance injections the maintenance interval was increased from 4 to 6 wk. IgG anti-yellow jacket venom antibodies did not change over the next 9 mo. The incidence of local reactions to venom injections did not increase, and there were no systemic reactions during therapy. After 6 to 9 mo 29 of the 30 patients were sting-challenged with one possible reaction. The success rate, 97%, is the same as that observed with monthly maintenance injections. We conclude that the 6-wk maintenance interval is effective in both clinical and immunologic terms after a period of monthly maintenance therapy.

Treatment failures with whole-body extract therapy of insect sting allergy.

Whole-body extracts (WBEs) remain in widespread use for therapy of insect sting anaphylaxis two years after the approval of Hymenoptera venoms. We have reviewed our experience with WBEs in our patient population. Of 250 patients who received WBE, 115 had subsequent stings. Systemic allergic reactions occurred in 65% large local reactions in 23%, and no reaction in 12%. There was no consistent change in the severity of systemic reactions during WBE treatment. Systemic reaction occurred less commonly in younger persons or after at least two years of WBE treatment. We conclude that WBE is not effective for the prevention of allergic insect sting reactions. The natural history of the disease may account for its apparent efficacy in young people or those having prolonged WBE therapy. Venom immunotherapy is safe and rapidly effective and is the only protective treatment recommended.

Psyllium laxative-induced anaphylaxis, asthma, and rhinitis.

A 69-year-old nurse was evaluated for a recent episode of anaphylaxis that had occurred after psyllium ingestion. She had experienced recurrent rhinitis and asthma related to psyllium exposure for the past 15 years. The diagnosis of psyllium hypersensitivity was established by a positive psyllium puncture skin test, an elevated psyllium-specific IgE level in serum, and a confirmatory soluble-antigen competitive inhibition test. The patient was symptomatic for several years, and this diagnosis was not considered until she suffered potentially life-threatening anaphylaxis. Psyllium hypersensitivity may be a more common phenomenon than is currently appreciated by physicians and other health-care providers.

Allergy to insect sting. III. Allergenic cross-reactivity among the vespid venoms.

Recent reports have indicated that venoms may be more beneficial than whole body extracts for the diagnosis and treatment of Hymenoptera sensitive patients. These studies were undertaken to determine the cross-reactivity among the vespid venoms. Eighteen patients who were anaphylactically sensitive to vespid venoms were studied using in vitro leukocyte histamine release. The results (venom concentration for 50% histamine release) were analyzed by linear regression analysis; there was no allergenic cross-reactivity between any of the venoms, except for a modest association between yellow hornet and white hornet venom. In spite of this result 13 of the 18 patients studied were sensitive to three or four of the venoms tested. There is no clear explanation for this observation, but it suggests the existence of multiple major allergens in the vespid venoms, some of which are cross-reactive. Since immunotherapy with inappropriate proteins may lead to the development of IgE and the possibility of clinical sensitivity and since the majority of patients were not sensitive to all venom preparations, we suggest that appropriate diagnostic studies be carried out before the institution of therapy.

Measurement of IgG-blocking antibodies: development and application of a radioimmunoassay.

A radioimmunoassay for measuring blocking antibodies has been developed. We used the ragweed antigen E system to show that the same blocking antibodies (IgG) measured by inhibition of antigen-induced leukocyte histamine release were precipitated in the binding assay (r8 = 0.96, p less than 0.001), thus validating a widely applicable technique for measuring blocking antibodies. Binding of phospholipase-A (Phos-A), the major allergen in honey bee venom, was also shown to correlate significantly with inhibition of histamine release. Hymenoptera (insect) hypersensitivity was used as a model to demonstrate application of the binding assay. Sera obtained from patients undergoing whole body extract therapy contained negligible amounts of specific blocking antibodies. Significantly higher blocking antibody titers to both whole honey bee venom and Phos-A were measured in sera drawn from patients immunized with whole venom. The use of the binding radioimmunoassay should facilitate management of allergic disease processes in which blocking antibodies are thought to be protective.

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.

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.

Effects of a single-dose pretreatment with captopril on the immediate response to nasal challenge with allergen.

We performed a double-blind, placebo-controlled, crossover study using 12 subjects to determine the effects of a single 50-mg dose of captopril on the response to nasal challenge with increasing doses of allergen. Levels of kinins, histamine and N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity were measured in nasal lavages, and symptom scores and the number of sneezes were recorded. Captopril had no significant effects on histamine, TAME-esterase, sneezing or symptom scores. Peak postchallenge kinin levels, however, were significantly elevated (p less than 0.05) compared to placebo, while an increase in the magnitude of the dose-response curve was of marginal significance (p = 0.058). Thus, captopril causes increases in the kinin levels in nasal secretions during the allergic response. If increased kinin levels persist or worsen with chronic therapy, it is possible that they could exacerbate allergic symptoms during repeated seasonal exposure.