David B.K. Golden

Allergy diagnostic testing: an updated practice parameter.

I. Leonard Bernstein, MD; James T. Li, MD, PhD; David I. Bernstein, MD; Robert Hamilton, PhD, DABMLI; Sheldon L. Spector, MD; Ricardo Tan, MD; Scott Sicherer, MD; David B. K. Golden, MD; David A. Khan, MD; Richard A. Nicklas, MD; Jay M. Portnoy, MD; Joann Blessing-Moore, MD; Linda Cox, MD; David M. Lang, MD; John Oppenheimer, MD; Christopher C. Randolph, MD; Diane E. Schuller, MD; Stephen A. Tilles, MD; Dana V. Wallace, MD; Estelle Levetin, PhD; and Richard Weber, MD

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.

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.

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.

Anaphylaxis--a practice parameter update 2015.

Phillip Lieberman, MD; Richard A. Nicklas, MD; Christopher Randolph, MD; John Oppenheimer, MD; David Bernstein, MD; Jonathan Bernstein, MD; Anne Ellis, MD; David B.K. Golden, MD; Paul Greenberger, MD; Steven Kemp, MD; David Khan, MD; Dennis Ledford, MD; Jay Lieberman, MD; Dean Metcalfe, MD; Anna Nowak-Wegrzyn, MD; Scott Sicherer, MD; Dana Wallace, MD; Joann Blessing-Moore, MD; David Lang, MD; Jay M. Portnoy, MD; Diane Schuller, MD; Sheldon Spector, MD; and Stephen A. Tilles, MD Chief Editors: Phillip Lieberman, MD; Richard A. Nicklas, MD; John Oppenheimer, MD; Christopher Randolph, MD Members of the Joint Task Force: David Bernstein, MD; Joann Blessing-Moore, MD; David Khan, MD; David Lang, MD; Richard Nicklas, MD; John Oppenheimer, MD; Jay M. Portnoy, MD; Christopher Randolph, MD; Diane Schuller, MD; Sheldon Spector, MD; Stephen A. Tilles, MD; Dana Wallace, MD Practice ParameterWorkgroup: David Bernstein, MD; Jonathan Bernstein, MD; Anne Ellis, MD; David B.K. Golden, MD; David Khan, MD; Dennis Ledford, MD; Jay Lieberman, MD; Dean Metcalfe, MD; Dana Wallace, MD

Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force.

The intended purpose of this monograph is to provide a general overview of allergy diagnostics for health care professionals who care for patients with allergic disease. For a more comprehensive review of allergy diagnostic testing, readers can refer to the Allergy Diagnostic Practice Parameters. A key message is that a positive allergy test result (skin or blood) indicates only the presence of allergen specific IgE (called sensitization). It does not necessarily mean clinical allergy (ie, allergic symptoms with exposure). It is important for this reason that the allergy evaluation be based on the patients history and directed by a health care professional with sufficient understanding of allergy diagnostic testing to use the information obtained from his/her evaluation of the patient to determine (1) what allergy diagnostic tests to order, (2) how to interpret the allergy diagnostic test results, and (3) how to use the information obtained from the allergy evaluation to develop an appropriate therapeutic treatment plan.

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.

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.