Practical allergy (PRACTALL) report: risk assessment in anaphylaxis.

Effector mechanisms in anaphylaxis were reviewed. Current approaches to confirmation of the clinical diagnosis were discussed. Improved methods for distinguishing between allergen sensitization (which is common in the general population) and clinical risk of anaphylaxis (which is uncommon) were deliberated. Innovative techniques that will improve risk assessment in anaphylaxis in the future were described.

Case report of venom immunotherapy for a patient with large local reactions.

BACKGROUND: Inadvertent Hymenoptera stings reportedly elicit large local reactions in up to 17% of the general population. Current practice parameters do not recommend venom immunotherapy (IT) for these cases. OBJECTIVE: The goal of this case study was to investigate the clinical and immunologic consequences of venom IT in a newly sensitized individual with large local reactions using an intentional sting challenge before and after treatment to document changes in reaction severity. METHODS: A 47-year-old man became honeybee venom (HBV)-allergic with progressively larger reactions at honeybee sting sites with subsequent stings. Then, a sting on his forefinger produced a large (62 cm) local reaction with swelling throughout the arm that persisted for more than 4 weeks with severe pain. He refused steroid therapy and voluntarily requested venom IT with honeybee-sting challenges to monitor clinical parameters and immunologic changes in his skin and serum before and 7 months post-HBV maintenance IT. RESULTS: A single pre-IT bee sting challenge produced an 11.4-cm wheal with 13-cm erythema at the sting site after 15 minutes, followed by several weeks of edema that involved the entire arm. After rapid escalation of venom IT to maintenance in 7 weeks, a post-maintenance IT sting challenge with two honeybees produced a 3-cm diameter erythema with no wheal at 15 minutes and no late-phase induration. Complete loss of any visible reaction at the field sting site resulted after 13 months of maintenance venom IT. A HBV-specific IgG antibody level >3.5 microg/mL and IgG/IgE antibody molar ratio >500 persisted over the period of venom IT, with venom skin reactivity diminishing 100-fold. CONCLUSIONS: These results support venom IT use in the treatment of Hymenoptera venom-sensitive individuals who experience large local reactions and are at risk for repetitive inadvertent stings.

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.

Discontinuing venom immunotherapy.

The decision to discontinue venom immunotherapy requires a great deal of clinical judgement because of the potential for a life-threatening reaction to a sting. The risk of recurrence is a combination of the frequency of reaction and the severity of reaction. Early studies reported a relapse rate of 8-14% in radioallergosorbent test-negative patients when therapy was stopped after 3 years. Unfortunately, the venom skin test or radioallergosorbent test becomes negative in only 25% of patients after 5 years of treatment. An alternative criterion for stopping treatment after 5 years regardless of the skin test has been equally successful, with most post-treatment reactions being much milder than pre-treatment reactions. There was no evidence of a rebound of venom sensitivity when therapy was stopped, even when patients were stung. The level of venom-specific IgE antibodies is better suppressed by 5 than by 3 years of treatment. The risk of relapse is higher in honeybee-allergic patients and in patients who had a systemic reaction (to a sting or an injection) during therapy. The frequency of reaction may be low, but patients who had very severe pre-treatment reactions have a greater chance of the reaction being severe again, and should remain on therapy for life. Long-term observations show that the incidence of systemic reaction to a sting remains 10% for each sting that occurs, even 10-15 years after stopping treatment. Because patients may not react to one sting and then subsequently react to another sting, the cumulative frequency of sting reactions is approximately 17% after 10 years off treatment. Moreover, negative venom skin tests are not a guarantee of safety because there is almost the same 10% frequency of reaction in patients who appear to lose sensitivity. It is not yet clear whether some low-risk patients (children, mild reactors) could discontinue treatment after just 3 years.

Survey of patients after discontinuing venom immunotherapy.

BACKGROUND: Venom immunotherapy rapidly reduces the risk of a systemic sting reaction in adults from 30% to 70% to less than 2%. When venom immunotherapy is stopped after 5 years or longer, the risk of a systemic sting reaction is 5% to 15% during the first few years after stopping treatment. It is uncertain whether systemic sting reactions will occur more than 5 years after discontinuing venom immunotherapy and whether treatment can be safely stopped in some patients after less than 5 years. OBJECTIVE: The purpose of this study is to estimate the risk of systemic reaction to a sting 10 years after discontinuing treatment and the relative risk after 3 years of treatment compared with that after 5 years or more of treatment. METHODS: Among all patients who had venom immunotherapy at our center, we identified 395 patients who stopped treatment: some had dropped out of therapy early (6-24 months), some stopped after 3 to 4 years, and most completed 5 years or more of venom immunotherapy and were advised to stop by the allergist (many as part of our reported studies of discontinuing venom immunotherapy). RESULTS: Contact was made with 194 patients, including telephone interviews for sting history and requests to visit the office for skin testing and blood sampling. Of these patients, 74 had been included in our original study of patients who had 5 years or more of venom immunotherapy and had sting challenges after 1 to 5 years off venom immunotherapy, as previously reported. Of the 74 in that original study, 61 were reached for this survey, and 30 reported recent stings, with 5 systemic sting reactions. Another 133 patients who had stopped venom immunotherapy were reached: 82 had 5 or more years of venom immunotherapy, 20 had 3 to 4 years of venom immunotherapy, and 31 had less than 2 years of venom immunotherapy. Of 51 patients stung from this group, 27 had 5 or more years of venom immunotherapy (no systemic sting reactions), and 24 had less than 5 years of venom immunotherapy (3 systemic sting reactions). We have now observed a total of 113 patients who had 5 or more years of venom immunotherapy and were stung after stopping. Sixteen (14%) had systemic sting reactions; most were mild, but 4 were severe. Systemic sting reactions occurred in 12 (10.7%) of 112 patients stung in the first 4 years off venom immunotherapy and 5 (10%) of 50 stung more than 5 years off venom immunotherapy. In 4 of 8 patients with current systemic sting reactions, the skin test response was negative, although the venom-IgE response was positive at the previous encounter. All systemic sting reactions were similar in pattern and severity to prevenom immunotherapy reactions in the same patient. CONCLUSIONS: We conclude that the risk of systemic sting reactions when venom immunotherapy is stopped after 5 years or longer remains in the reported range of 5% to 15% in the 5 to 10 years after stopping venom immunotherapy. This risk of systemic sting reactions does not seem to decrease over time, unlike the progressive decline in immunologic markers (skin test and venom-IgE responses). To prospectively assess the risk of recurrent systemic sting reactions, there is a need for sting challenge studies of patients who have been off venom immunotherapy for 5 to 10 years and patients who have stopped venom immunotherapy after just 3 to 4 years treatment.

Discontinuing venom immunotherapy: extended observations.

BACKGROUND: Our studies of discontinuing venom immunotherapy after at least 5 years have led to the conclusion that the residual risk of a systemic reaction to a sting was in the range of 5% to 10% in adults, and no severe or life-threatening reaction occurred with 270 challenge stings in 74 patients after 1 to 5 years without venom immunotherapy. OBJECTIVE: The objective of this study was to extend our observation of patients who discontinue venom immunotherapy over 5 to 10 years and to determine which patients are at higher risk for a reaction. METHODS: Patients who discontinued venom immunotherapy were surveyed for 3 consecutive years to determine the frequency of systemic reactions to field stings and the fate of venom sensitivity. The evaluation included the 74 patients previously studied (group 1) and 51 additional patients followed after stopping therapy in our clinical center (group 2). RESULTS: Of the original 74 patients, 11 had field stings again after 3 to 7 years without venom immunotherapy, with one systemic reaction (dyspnea). Of the 51 patients in the other group, 15 were stung, of whom four (26%) had systemic reactions, including respiratory symptoms requiring epinephrine. Review of group 1 and group 2 revealed that half of the patients who had systemic reactions to a sting after stopping venom immunotherapy had a history of a systemic reaction occurring during venom immunotherapy (to an injection or a sting). Systemic reactions occurred in three patients who had negative skin test reactions; all three had very low but detectable venom-specific serum IgE antibody levels as determined by RAST and had a history of systemic reactions during venom immunotherapy. Greater severity of the pretreatment reaction was not associated with higher frequency of reaction to stings after stopping therapy but was associated with greater severity if a reaction did occur. CONCLUSIONS: Venom immunotherapy (yellow jacket/mixed vespid) in adults can be discontinued after 5 to 6 years with a 5% to 10% residual risk of a systemic reaction. Risk factors may include history of a systemic reaction during venom immunotherapy, persistent strongly positive skin test sensitivity, and the severity of the pretreatment reaction.

Natural history of Hymenoptera venom sensitivity in adults.

BACKGROUND: Epidemiologic studies of Hymenoptera venom allergy in adults show a prevalence of positive venom skin test results, RASTs of 15% to 25%, or both, but most such individuals have had no systemic reactions to stings. The clinical significance and natural history of this apparently common sensitivity is uncertain. OBJECTIVE: We sought to determine the natural history of venom sensitization by observing the rate of decrease or increase in sensitivity in normal adults over 5 to 10 years. The clinical significance of these findings is related to the frequency of systemic reactions to stings during the period of observation. METHODS: Serial observations were planned in 520 volunteers and randomly selected subjects. Two follow-up visits were attempted, once after 2 to 3 years and again after 5 to 9 years, to perform repeat venom skin tests and RASTs and to review any history of interim stings and their outcomes. RESULTS: Follow-up visits were conducted with 398 subjects (375 early visits and 205 late visits). Overall, in the 398 subjects with one or more visits after a mean of 4 years, skin test responses changed from positive to negative in 44 of 98 (45%) and from negative to positive in 27 of 309 (8.7%) of the subjects. Skin test responses changed from positive to negative in 29 of 87 (33%) subjects after 2.5 years and in 43 of 54 (80%) after 6.8 years. Even when the skin test response became negative, venom-specific IgE remained positive in 11 of 29 (38%) subjects after 2.5 years and in 13 of 43 (30%) after 6.8 years. The rate of loss of sensitivity was 12% per year, similar to retrospective estimates. Skin test sensitivity to venoms disappears more rapidly in these subjects without symptoms (half-life, 4 years) than in patients receiving venom immunotherapy (half-life, 7 years). Skin test responses changed from negative to positive in 23 of 288 (8%) subjects after 2.5 years and in 9 of 151 (6%) after 6.8 years. Insect stings caused no reaction in 120 subjects with a negative skin test response, but 17% (11 of 65) of subjects with a positive skin test response (but with a negative history) had systemic reactions when stung. There was no difference between the early and late visits in the frequency of systemic reactions reported. The risk may be higher than 17% for the specific individuals (67% after 2.5 years and 20% after 6.8 years) whose positive skin test responses persist for years. This risk is lower than that of patients with a positive history (50%) but higher than that of "normal" adults or venom-treated patients (<2%). It is still not clear whether any subset of adults with a positive skin test response but a negative history can be identified, in whom the risk of systemic sting reaction would justify venom immunotherapy even before any reaction occurs. CONCLUSION: Asymptomatic venom sensitization in adults is common but transient, disappearing at the rate of 12% per year. However, the risk of a systemic reaction to a subsequent sting is significant in adults without symptoms but with positive venom skin test responses (17%) and may be higher when skin test sensitivity does persist for years.

Discontinuing venom immunotherapy: outcome after five years.

BACKGROUND: The 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. METHODS: Sting 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. RESULTS: Systemic 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. CONCLUSIONS: Venom 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.

Selection of Hymenoptera venoms for immunotherapy on the basis of patient's IgE antibody cross-reactivity.

BACKGROUND: Positive skin test results to multiple venoms in patients with Hymenoptera venom allergy may result from IgE antibody cross-reactivity among venom proteins. To avoid treatment with unnecessary and costly venoms, we have developed a venom RAST inhibition test that identifies individuals in whom a positive venom IgE RAST result is due to cross-reactive venom-specific IgE antibody. METHODS: Serum samples (n = 412) were collected over 5 years from patients with clinically characterized Hymenoptera venom allergy who had positive skin test results to more than one venom. Venom allergosorbent was added to serum containing IgE antivenin and buffer or 100 micrograms of homologous or heterologous venom. Bound IgE was detected with radiolabeled anti-human IgE. Intraassay variation less than 10% coefficient of variation and homologous venom inhibition greater than 80% were required for acceptance of data. A "cross-reactivity index" (CRI) was computed as a ratio of percent inhibition produced by heterologous versus homologous venom. RESULTS: Of the 412 sera-venom combinations analyzed, 41 (10%) were excluded because of incomplete homologous venom inhibition. Of the 371 remaining sera, 82% (n = 305) were studied for IgE anti-Polistes wasp venom (PWV) cross-reactivity with yellow jacket venom (YJV) and the other 66 for other venom specificity cross-inhibitions. Of the serum samples tested, 36.4% (111 of 305) contained IgE anti-PWV venom of which the binding to solid-phase PWV was inhibited with soluble YJV to a level that produced CRIs greater than 95%. We believe that this constitutes complete inhibition and demonstrates exclusively YJV cross-reactive antibody in these samples. The remaining 63.6% had CRIs from 0% to 95%, indicating IgE specific for a spectrum of unique and cross-reactive PWV allergens. Only 4.3% (13 of 305) had CRIs less than 5%, which is consistent with IgE restricted to PWV unique allergens. The degree of the IgE anti-PWV inhibition to solid-phase PWV by YJV was independent of the IgE anti-PWV level. CONCLUSIONS: This study shows that one third of patients with Hymenoptera venom allergy evaluated with positive YJV- and PWV-reactive IgE in the skin and/or serum were identified as candidates for exclusion of PWV from their immunotherapy regimen because their IgE anti-PWV was more than 95% cross-inhibitable with YJV. Cost analysis of the venom RAST inhibition test and a conventional 5-year Hymenoptera venom immunotherapy program indicates that this serologic evaluation is cost-effective.

Suggested approaches for research protocols involving the potential for life-threatening reactions.

These guidelines are intended to reduce the potential for serious or life-threatening reactions when clinical research is conducted. The following issues were addressed: identifying the risks involved in the research, providing adequate safeguards in the protocol design and during withholding of medication, anticipating risks, minimizing the chances for human error, providing resuscitative equipment sufficient to deal with the most serious anticipated life-threatening reactions, planning for medical support in case of a life-threatening emergency, and optimizing the use of medical personnel and expertise to handle emergency situations. The guidelines also discuss important general issues about protocol design and implementation and the human subject consent form, which should facilitate the approval of protocols by the governing institutional review board. The guidelines are not meant to be inflexible or applicable to all research situations. However, it is our hope that they will allow for clinical research to be conducted in a manner that affords the research subjects a high degree of protection from unnecessary and possibly fatal injuries.

Clinical correlation of the venom-specific IgG antibody level during maintenance venom immunotherapy.

Allergen immunotherapy is associated with a significant increase of specific IgG antibodies that have been suggested as a mechanism of action and as a marker of efficacy for immunotherapy. The value of venom-specific IgG antibody determinations as a measure of clinical protection against sting anaphylaxis has been difficult to prove in individual patients. We performed 211 insect sting challenges in 109 patients over a 4-year period to determine the significance of venom IgG levels 3 micrograms/ml or lower. Systemic symptoms occurred in only 1.6% of those with venom IgG more than 3 micrograms/ml, but in 16% of those with less than 3 micrograms/ml IgG, and notably in 26% of patients with low venom IgG who had received less than 4 years of treatment. The venom IgG level had no predictive value in patients who had received more than 4 years of therapy. Honeybee sting data were inconclusive because of the small number of subjects. We conclude that low venom-specific IgG levels are associated with an elevated risk of treatment failure during the first 4 years of immunotherapy with yellow jacket or mixed vespid venoms.

Venom immunotherapy in the Hymenoptera-allergic pregnant patient.

Natural or iatrogenic causes of anaphylaxis are significant risk factors in pregnancy. A 3% to 5% risk of sting anaphylaxis in any pregnant woman with insect-sting allergy untreated with venom immunotherapy (VIT) can be calculated. Insect-sting anaphylaxis has allegedly caused severe fetal abnormalities and is a potential cause of fetal loss and severe maternal morbidity and/or mortality. Hymenoptera anaphylaxis is a highly preventable cause of anaphylaxis, but VIT may itself carry a risk potential, with an appropriate 5% reaction during buildup and 1% reaction risk during maintenance VIT. To assess the safety of VIT in pregnancy, we have gathered data from 26 women with 43 pregnancies. All the women were receiving VIT. One woman was stung early in pregnancy with anaphylaxis resulting. Outcome of pregnancy was normal. Thirty-six of the pregnancies ended normally. There were two mild adverse reactions to VIT, neither of which required treatment. One child was born with multiple congenital abnormalities of unknown cause. Since congenital malformations may occur as frequently as one in 40 live births, these data do not suggest a significant increased risk from VIT during pregnancy.

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.