Venom Skin Tests Research Articles

Unusual Reactions to Insect Venoms

A variety of unusual, unexpected reactions have been described that occur in a temporal relationship to venom exposure, primarily insect stings. An immunologic mechanism appears responsible for reactions such as serum sickness and late onset allergiclike symptoms. In all probability, allergic mechanisms are responsible for the renal and neurologic symptoms and the delayed hypersensitivity type reactions. The mechanisms for the fatigue and malaise following venom injections and the most unusual areas of extensive erythema following venom skin tests are not known.

Clinical and immunologic follow-up of patients who stop venom immunotherapy

We prospectively studied 51 self-selected Hymenoptera sting-sensitive patients to determine (1) whether a minimal or optimal duration for venom immunotherapy (VIT) exists and (2) whether clinical or immunologic parameters exist that are predictive of clinical immunity after VIT was stopped. After 2 to 10 years of VIT, all patients had deliberate sting challenges (DSCs) from live insects. If DSCs were tolerated, patients voluntarily stopped VIT and returned annually for repeat venom skin tests (VSTs) and DSCs. In most patients, it was possible to monitor VST and venom-specific antibody (Ab) levels before and after VIT was stopped. One-year after VIT, VST and venom-specific IgE and IgG Ab level results were variable; 49 patients tolerated DSC, whereas two patients exhibited generalized reactions. These two patients had pre-VIT histories of grade IV field-sting reactions and had received VIT for 2 years and 4 years, respectively. The short-term (1 year) risk of recurrence of clinical allergy to stings after VIT was higher in patients who had experienced grade IV field-sting reactions before VIT versus patients experiencing grade I to III reactions before VIT ( 2 15 , 13% versus 0 36 , 0%) and higher in patients who had received VIT for less than 5 years versus patients who received VIT for 5 or more years (2/20, 10% versus 0/31, 0%). We suggest that VIT should be continued for 5 years in patients with pre-VIT field-sting reactions of grade IV severity. VST and venom-specific Ab results do not reliably predict the outcome of DSC or the subsequent clinical course in individual patients stopping VIT.

Stinging insect allergy

Insect stings occur commonly, with clinical responses ranging from mild local reactions to life-threatening anaphylaxis. Stings from Hymenoptera (yellow jackets, hornets, wasps, honey bees, and imported fire ants) account for the majority of severe allergic reactions to insects. Patients who present with a systemic reaction should receive emergency therapy and be provided with self-injectable epinephrine (Epi-Pen®) until definitive treatment can be provided. Anaphylactic symptoms and hypotension may be prominent in persons taking beta adrenergic blockers and may necessitate vigorous treatment. The diagnosis of Hymenoptera hypersensitivity can be established by venom skin testing. In more than 95% of cases, immunotherapy with specific venom is effective in preventing subsequent systemic reactions to Hymenoptera stings.

The Hymenoptera venom study III: Safety of venom immunotherapy

One thousand four hundred ten (44%) of the 3236 subjects in the Hymenoptera venom study accepted venom immunotherapy (VIT). Time to maintenance averaged 95 days, and the largest number achieved maintenance (147 subjects, 10.4%) at day 56. Ninety-two percent of the treated subjects achieved maintenance, and 84% continued therapy, most subjects (91%) until the study was terminated. One hundred seventy-one subjects (12%) experienced 327 treatment systemic reactions (Srs). The incidence of pruritus and angioedema/urticaria was similar with mild, moderate, or severe SRs. The SR severity did not correlate with the severity of the most recent sting before entry into the Hymenoptera-venom study, the most severe historical sting SR, the most severe SR during venom skin tests, the total dose of venom, the degree of skin test reactivity, or the lowest concentration yielding a positive skin test. Most SRs occurred between 1 and 50 micrograms and at maintenance; honeybee or wasp venoms were most likely to produce SR. This study, the largest of its kind with the use of standardized extracts, demonstrates (1) that there was good compliance, (2) that various historical and diagnostic criteria did not predict SRs to VIT, (3) that SRs to VIT were most likely to occur between 1 and 50 micrograms and at maintenance, (4) that honeybee or wasp venoms were most likely to produce an SR, and (5) that VIT is relatively safe.

The Hymenoptera venom study II: Skin test results and safety of venom skin testing

Data are summarized in this Hymenoptera venom study (HVS) article on the safety of skin testing with venom extracts. Of the 3236 subjects studied, 89% had experienced an historical sting systemic reaction (SSR). Seventy-four percent of all subjects and 76% of subjects who had experienced an historical SSR had a positive skin test to at least one venom. More subjects tested positive to yellow jacket venom (51.8%) than to any other venom. There were no significant differences of the wheal and erythema sizes associated with different venoms or different historical sting reactions. Forty-five percent of subjects with positive venom skin tests (VST) were positive to wasp, and 89% of these subjects were also positive to at least one of the following venoms: yellow jacket, yellow hornet, or white-faced hornet. Sixty-four of the 3236 subjects studied (2%) had a systemic reaction (SR) during VST; 13 of the SRs (0.4%) were severe. Thirteen of 64 adverse reactions (20%) were possibly vasovagal, and six other subjects (9%) demonstrated no symptoms of immediate-type hypersensitivity. Thus, 45 (1.4%) of the 3236 subjects tested had an SR that was considered to be a reaction of hypersensitivity, of which eight reactions (0.25%) were severe. Allergic SRs are associated with VST but are unusual and are rarely severe.

Anaphylaxis from insect stings. Myths, controversy, and reality.

Some myths and controversies regarding allergy to insect stings have been resolved through research, and venom immunotherapy now has an important place in the prevention of life-threatening reactions to stings. Both children and adults who had cardiovascular and/or respiratory reactions to their most recent sting are candidates for this treatment, which should be discontinued at the end of 5 years (or sooner, if venom skin tests or radioallergosorbent tests are negative).

Epidemiology of Insect Venom Sensitivity

The prevalence of insect sting reaction and of venom sensitization in adults is unknown. We report the results of intake evaluation of a stratified random sample of a large adult population previously studied for the determinants of atopic disease. In 269 subjects, the prevalence of systemic allergic sting reactions was 3.3% and 26.5% had IgE antibodies to venom demonstrated by skin test or radioallergosorbent test. Asymptomatic sensitization (positive venom skin test) was observed in 15% of subjects with no history of an allergic sting reaction. Positive venom skin tests were more frequent in men, in those with positive skin tests to inhalant allergens, and in subjects aged 20 through 29 years. A positive venom skin test or radioallergosorbent test was more frequent in subjects who had been stung within the previous 3 years (35%) than in those stung more than 3 years before (20%). We conclude that both systemic allergic reactions to insect stings and asymptomatic sensitivity to venom are common and that most affected persons never seek medical advice. The significance of asymptomatic venom sensitization is unknown.

Evolution of sensitivity to hymenoptera venoms during maintenance immunotherapy.

Duration of venom immunotherapy still remains questionable since some patients lose their sensitivity. Venom immunotherapy can be stopped when venom skin tests and specific IgE are negative. Five studies have been performed to prospectively study the evolution of skin tests and specific IgE after three to six years of maintenance immunotherapy. Four studies showed that skin tests became negative in 30 to 55% of patients depending upon the venom species and the duration of the treatment. Mean specific IgE declined in most studies but were negative only in a substantial number of patients in the European studies. Adults and children had a similar rate of disappearance of skin test reactivity. In one study, skin tests were negative in 1/3 of patients after one year of treatment suggesting that venom immunotherapy may be given for a short period of time in some patients.

A study of the prevalence and clinical significance of venom-specific IgE

The prevalence of unrecognized Hymenoptera-venom sensitization, assessed by venom skin tests (VSTs) in adults with no history of adverse reactions to sting, has been as high as 12% in previous epidemiologic studies. To assess further the clinical importance of positive VSTs in such individuals, we skin tested 33 subjects stung in the field during the preceding 12 months without reaction, and 33 persons who denied being stung in the preceding 3 years. Among the recently stung gruop, 12 33 had at least one positive VST (⩾2 +) at 1.0 μg/ml, whereas 5 33 had positive VST at 0.1 μg/ml. In contrast, only 2 33 nonstung subjects had positive VST at 1.0 μg/ml, and none were positive at 0.1 μg/ml. To estimate, prospectively, the sensitization rate after insect stings, we studied a third group of 11 nonsensitive patients with negative skin tests to Hymenoptera. After a deliberate in-hospital honeybee sting, only 1 11 developed a persistently positive honeybee VST. From among the three groups, we then performed nine sting challenges in eight patients with positive VSTs, and all stings were tolerated without significant reaction. We also measured IgE antibodies to Hymenoptera venoms in random blood bank donors. During April to May, 2 216 sera contained elevated venom-specific IgE antibodies, whereas 14 201 sera collected from October to November contained elevated venom-specific IgE antibodies. We conclude that a small but appreciable portion of the population has venom-specific IgE antibodies and that the prevalence is seasonably variable. Our data indicate that persons recently stung without significant reaction contribute to this group but that only a small portion of this group is at risk for a systemic reaction with a future sting.

Studies of the natural history of stinging-insect allergy: Long-term follow-up of patients without immunotherapy

This study reports the clinical and immunologic responses of 29 patients who were observed during a prolonged period after insect-sting anaphylaxis without venom immunotherapy. At the time of their initial evaluation, all patients had venom-specific IgE, detected by skin test or RAST. Their mean age was 21 years; 16 patients were 16 years of age or less. There were 18 male and 11 female patients. Eleven patients had urticaria and angioedema as their only symptoms of anaphylaxis, and 18 patients had respiratory and/or cardiovascular symptoms. Reassessment was done 5 or more years after the initial evaluation. The average time at reevaluation was 10.1 years after the initial sting reaction. There had been 25 re-stings in 17 patients, with three systemic reactions occurring in two patients, an overall reaction rate of 12%. The time interval between the initial sting reaction and the follow-up sting was 2 to 14 years, mean 7.3 years. In patients with initial urticaria/angioedema symptoms only, there were 11 re-stings with no reactions. In patients with initial cardiovascular/respiratory symptoms, there were 14 re-stings with three reactions. At the time of follow-up evaluation, venom-specific IgE had generally decreased. In six of 25 patients, venom skin tests became negative, and in eight of 24 patients, the RAST became negative. These observations suggest that in many patients, stinging insect allergy is a self-limited process, with loss of clinical sensitivity and immunologic reactivity.

Stinging insect allergy. Avoidance, identification, and treatment.

The incidence of anaphylaxis from insect stings is about 0.4%, most commonly caused by Hymenoptera species. Diagnosis is aided if the patient can reliably identify the insect, and more specific diagnosis depends on venom skin testing for individual sensitivity. Radioallergosorbent testing is also used but fails to identify about 15% to 20% of sensitivities. Avoidance of high-risk situations is the best approach for patients with known sensitivity. Treatment includes relief of local symptomatic reactions, pharmacologic arrest of anaphylaxis, and venom immunotherapy.

Assessment of prolonged venom immunotherapy in children

Venom immunotherapy was initiated in 94 children from April 1977 to October 1979. As of February 1983, 66 children had continued receiving treatment and had recent immunologic evaluation. Assessment of prolonged venom treatment included analysis of immunologic parameters, efficacy of treatment, and long-term safety. Venom skin tests, venom-specific IgE antibody levels, and venom-specific IgG antibody levels comprised the immunologic parameters evaluated. A decrease in allergic sensitivity was demonstrated over time in the skin and serum. Forty-three of 57 (75%) children had less positive vespid venom skin tests, and the mean venom-specific IgE antibody level declined to less than the pretreatment value with 3 or more years of yellow jacket venom therapy. Venom-specific IgG antibody measurements rose rapidly after the initiation of venom injections and were maintained for the duration of this evaluation. During a 3- to 6-year period, 200 stings in 49 treated children resulted in only four mild systemic reactions (98% efficacy). The benign nature of interval histories, physical examinations, and laboratory analyses in these children argues optimistically for the safety of prolonged venom immunotherapy.

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 μg/ml) to levels typical of untreated patients at the time of retesting (mean 1.95 ± 0.3 μg/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.

Venom skin tests in insect-allergic and insect-nonallergic populations

Intradermal skin tests with varying concentrations of honeybee, yellow jacket, white-faced hornet, yellow hornet, and Polistes venoms were done on 85 patients with histories of insectsting anaphylaxis and on 56 insect-nonallergic subjects. Positive skin tests (wheal ⩾ 5 to 10 mm and flare ⩾ 11 to 20 mm) were present in 67 insect-allergic patients at venom concentrations ranging from 0.001 μg/ml to 0.1 μg/ml. Seven additional allergic patients had positive skin tests with the 1.0 μg/ml venom concentration. Twenty-six nonallergic subjects had positive skin tests at the venom concentration of 1.0 μg/ml, and two patients had positive skin tests at the lower venom concentrations (0.001 to 0.1 μg/ml). These results confirm venom skin tests as a highly sensitive method of detecting venom-specific IgE in the evaluation of patients with stinging-insect hypersensitivity. Since a large percentage of insect-nonallergic subjects reacted to the 1.0 μg/ml concentration, clinical judgment and further in vitro testing should be considered in the evaluation of patients who react only at this venom concentration.

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.

Natural history of large local reactions from stinging insects

In ongoing studies of the natural history of stinging-insect allergy, 133 patients with large local reactions have been evaluated over 8 yr; 79 patients returned for reevaluation. Based on RAST analysis with honeybee and vespid venoms, patients were divided into RAST-positive and RAST-negative groups. Sixty-six patients were RAST-negative with positive venom skin tests in 58%. Seventy-five restings in this group led to no systemic reactions and 74 large local reactions. At follow-up RASTs remained negative, and the incidence of positive skin tests was unchanged. Sixty-seven patients had detectable serum venom-specific IgE covering a wide range in antibody titers, indistinguishable from patients with systemic reactions. Twenty-four of 67 patients received venom immunotherapy (VIT). RAST titers decreased similarly in the VIT and untreated groups. There were 55 restings resulting in 40 recurrent large local reactions occurring in equal incidence in treated and untreated patients. One systemic reaction occurred in an untreated patient. In reviewing 118 patients with sting anaphylaxis, a previous large local reaction occurred in five. These results suggest that after repeat stings, patients with large local reactions tend to have subsequent large local reactions, regardless of the presence of venom-specific IgE or immunotherapy. There is small risk of anaphylaxis. Determination of serum venom-specific IgE by RAST or skin tests does not aid in treatment or in predicting prognosis. Thus skin tests are not necessary in patients who have had large local reactions, and venom immunotherapy is not indicated.

The development of negative skin tests in children treated with venom immunotherapy

Twenty-eight of 62 children (45%) with a history of sting-induced anaphylaxis and initially positive skin tests to venom(s) developed negative venom skin tests to one or more of the venoms used in their treatment after 3 yr or more of immunotherapy. Children who developed negative venom skin tests were less sensitive prior to treatment, as judged by venom skin tests and venom specific IgE antibody determinations, than children who maintained positive venom skin tests. Levels of venom-specific IgE antibodies declined with time in most children, but to lower levels in those with negative skin tests. Venom specific IgG antibody levels were similar in both patients with negative skin tests and those with persistently positive skin tests. The development of negative skin tests may reflect a loss of allergic sensitivity, which is sufficient to allow the physician to consider the discontinuation of venom injections.

Diagnosis of Polistes wasp hypersensitivity

Patients referred from the Houston, Texas, metropolitan area were evaluated for allergic reactions to insect stings. Forty-eight persons reported at least one systemic reaction caused by a Polistes paper-nest wasp sting. Honey bees, imported fire ants, and other types of Hymenoptera were identified in that order by 19 other subjects with systemic allergic reactions. Life-threatening airway obstruction and/or hypotension were noted by most of our patients. Wasp venom skin testing was positive in 65% of subjects reporting sensitivity to this insect. Skin testing was correlated quantitatively with basophil histamine release, and qualitatively with RAST assays using Polistes wasp venom. Venoms from common species of Polistes were highly cross-reactive as shown by RAST and basophil histamine release. Patients having a positive history and laboratory response (by skin testing, histamine release, or RAST) to Polistes wasp venom also were positive to bee venom about 20% of the time and to another vespid (hornet or yellow jacket) over 50% of the time.

Epidemiologic study of insect allergy in children. II. Effect of accidental stings in allergic children

One hundred eighty-one children with non-life-threatening reactions to insect stings and positive venom skin tests were randomized to treatment (53) or no-treatment (128) groups and followed up clinically and immunologically for at least two years to assess the results of accidental stings. Twenty-eight stings in 17 treated patients and 74 stings in 47 untreated children occurred, leading to one mild reaction in a treated patient, and eight in the no-treatment group (P = NS). No reaction was more serious than the original. Based on IgE antibody changes and skin test results, 87% of the untreated children were stung by an insect to which they had clinical sensitivity by skin test. Vespid skin test sensitivity decreased 10-fold or more in both treated (72%) and untreated (44%) children. Of those with increased sensitivity, congruent to 70% had been stung. These data indicate that the incidence of severe reactions on resting is low in insect-allergic children, and that the majority show decreased skin test sensitivity over time.

An epidemiologic study of insect allergy in children. I. Characteristics of the disease

Of 235 children with a history of allergic reactions to insect stings studied, 59 had severe life-threatening systemic reactions, 123 had mild, non-life-threatening systemic reactions, and 53 had large local reactions. The overall male-female ratio was 2:1. Venom skin tests were positive in approximately 89% of each group. Prior whole body extract therapy increased the likelihood of venom skin test reactivity to multiple insect venoms from 51 to 78%. Venom skin test results did not correlate with the severity of previous allergic reactions. One hundred and nine children with NLTR and positive venom skin tests were entered into one of two groups--venom immunotherapy or observation only. During the first six months the treatment group had the expected fourfold rise in venom-specific IgE antibody titers, whereas the observation group had a decline of the mean IgE titer. Patients in the observation group who were accidentally stung had a transient rise in IgE antibody titers. The small number of accidental stings which occurred in both groups resulted in reactions milder than the original reactions. Although based on preliminary data, venom immunotherapy may not be necessary for some children with previously mild systemic symptoms.