Ask the Expert : Phillip Lieberman, MD When to Discontinue Venom Immunotherapy: The Role of Retesting to Venom Phillip Lieberman, MD, and David Golden, MD For more Ask the Expert questions and answers, visit www.aaaai.org/ask-the-expert.aspx.
Question: I have a 60-year-old female patient with a history of venom hypersensitivity, allergic rhinitis, and mild asthma who has taken venom immunotherapy (VIT) at maintenance since 2005. When initially tested in 2003, she had demonstrated 4þ reactivity to wasp and 2þ reactivity to white hornet. She started venom immunotherapy at that time but discontinued them after approximately 9 months because of perceived delayed local reactions (she would complain of a sense of exterior neck swelling, although findings were never visible on examination). She was subsequently stung several times and had progressively worsening reactions, one of which required emergency department evaluation. After that episode, she elected to resume VIT in early 2005 and has tolerated it ever since without problem. She has had at least one sting since resuming VIT (she thinks it had been a wasp) which she tolerated with no symptoms. She wanted to know whether continued immunotherapy for stinging insects was warranted, and the option of updated testing was offered. Because she had been stung several times since the initial testing, the full panel of all stinging insects was completed. She had no change in response to the white hornet, a decreased response to wasp (2þ reactivity), but she now demonstrated 3þ reactivity to yellow jacket, 2þ to yellow hornet, and 1 to 2þ on honeybee (HB). An ImmunoCAP was then obtained, which showed moderate levels all of all stinging insects as follows: HB, 1.02 kUA/L; yellow hornet, 1.44 kUA/L; white hornet, 4.85 kUA/L; and common wasp, 1.73 kUA/L. (Yellow jacket was inadvertently omitted by the laboratory.) Do you think it is advisable to revise her current VIT to reflect these new sensitizations, essentially “restarting” her immunotherapy, or to continue her existing maintenance formula of the wasp and white hornet? She is willing to start over if it is recommended (this was before I had received the results of the serum testing). Thanks very much. Response: This question was posed to Dr. David Golden, MD, who responded as follows.
Conflicts of interest: David Golden has received clinical trial grants from Siemens Diagnostics and ALK-Abello. Available online February 5, 2013. Cite this article as: Lieberman P, Golden D. When to discontinue venom immunotherapy: The role of retesting to venom. J Allergy Clin Immunol: In Practice 2013;1:202-3. http://dx.doi.org/10.1016/j.jaip.2012.12.004. J Allergy Clin Immunol: In Practice 2013;1:202-3. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2012.12.004
202
Although most of our clinical decisions are based on the severity of the reactions to stings, this is a question about the diagnostic methods and the choice of venoms for immunotherapy. There are 3 possible explanations for the observed changes in venom sensitivity. First, the original tests may have missed some sensitivities. Venom skin tests are known to have some variability over time such that one of the venoms could be negative, but repeat tests weeks or months later could be positive (and the converse also occurs).1 So if tests are positive to some but not all venoms, it may be helpful to repeat skin tests or to check serum venom-IgE levels, before finalizing the selection of venoms for VIT. We cannot know at this time whether such additional tests would have showed additional sensitivities. Second, it is possible that the interval stings were from different species and caused neo-sensitization. Third, additional sensitivities could be due to immune responses to an expanded repertoire of antigenic epitopes during VIT.2 RAST inhibition tests could determine whether the vespid sensitivities in this patient are all cross-reactive or whether she has specific and unique sensitivities to multiple species.3 If they are cross-reactive, then her VIT with wasp and white hornet will cross-protect her against yellow jacket and yellow hornet. New sensitization to HB in a 60-year-old is most unlikely unless she gardens without gloves or walks barefoot in the grass. Dual sensitization to vespid and HB venoms is usually due to crossreacting carbohydrate determinants (CCDs). This type of crossreactivity can be distinguished by serologic testing with recombinant venom allergens (which are expressed without the CCD components).4-6 But in the end, unless we can prove in vitro that the new sensitivities are not clinically significant, I must return to my first statement: our clinical decisions are based on the severity of the reactions to stings. This requires more detailed information about the pattern of her reactions. It is not clear whether she had significant hypotension or airway obstruction. If she had such reactions, and they had become progressively more severe, I would be tempted to give her an additional 3 years of VIT with all 5 venoms. I could be persuaded to omit the HB venom if she promises not to garden without gloves or to walk barefoot in the grass. There are also a number of issues that arise in the patient’s original question about how long she needs to continue VIT, and how this question can be best answered. Patients who have had VIT at maintenance doses for 5 years or more are generally able to stop treatment and have about 10% chance of systemic reaction to each subsequent sting, even more than 10 years later, and even if venom skin tests become negative.7 If the patient is stung on several occasions over a period of years, the chance of reaction is increased.
J ALLERGY CLIN IMMUNOL: IN PRACTICE VOLUME 1, NUMBER 2
Almost all these reactions are much milder than the pre-VIT reaction. The chance of a systemic reaction and the chance of a severe reaction are associated with several “high-risk factors.” The chance of relapse (systemic reaction to a subsequent sting) is increased in patients who had systemic reactions during VIT (either to venom injections or to stings), in those with frequent exposure to stings, and in patients with allergy to HB.7 The chance of severe or fatal anaphylaxis is highest in patients with a history of severe (near-fatal) sting reactions or with elevated baseline serum tryptase or mastocytosis.8 The decision whether to stop VIT must take into account several factors. One must review the history of the original sting reaction and of the patient’s VIT for any evidence of high-risk factors. There should be a balanced discussion with the patient about the relative chance of reaction on discontinuing treatment, and how comfortable the patient is with the decision to stop. However, the decision cannot be made any easier by venom-IgE tests (skin or serum), and in fact, the results might complicate the decision as they did in this case. The level of sensitivity is not predictive of outcome, and even patients with negative skin tests have had relapses (even near fatal).9 So my opinion in this case may revolve around the exact nature of her “progressively more severe reactions” before VIT. If she had marked hypotension or respiratory distress, she should not stop VIT. If she had “mild-to-moderate” systemic reactions, and if we assume that her reaction to initial VIT were not true systemic reactions, then she should consider stopping VIT. Ideally, we would also check her baseline serum tryptase. Because her treatment included both Vespula and Polistes species, I feel the “new” vespid sensitivities are probably cross-reactive.
ASK THE EXPERT
203
Please understand that I can only express opinions that are based on the available information about the patient. Any recommendation specific for this patient must be based on the clinical judgment of the allergist who has directly evaluated the patient and had a personal discussion with the patient. REFERENCES 1. Graif Y, Confino-Cohen R, Goldberg A. Reproducibility of skin testing and serum venom-specific IgE in Hymenoptera venom allergy. Ann Allergy 2006;96:24-9. 2. Tavares B, Rodrigues F, Pereira C, Loureiro G, Chieira C. Development of new IgE specificities to hymenoptera allergens during venom-specific immunotherapy. Eur Ann Allergy Clin Immunol 2005;37:171-6. 3. Hamilton RH, Wisenauer JA, Golden DB, Valentine MD, Adkinson NF Jr. Selection of Hymenoptera venoms for immunotherapy based on patients’ IgE antibody cross-reactivity. J Allergy Clin Immunol 1993;92:651-9. 4. Muller UR, Johansen N, Petersen AB, Fromberg-Nielsen J, Haeberli G. Hymenoptera venom allergy: analysis of double positivity to honey bee and Vespula venom by estimation of IgE antibodies to species-specific major allergens Api m1 and Ves v5. Allergy 2008;64:543-8. 5. Eberlein B, Krischan L, Darsow U, Ollert M. Double positivity to bee and wasp venom: improved diagnostic procedure by recombinant allergen-based IgE testing and basophil activation test including data about cross-reactive carbohydrate determinants. J Allergy Clin Immunol 2012;130:155-61. 6. Sturm GJ, Hemmer W, Hawranek T, Lang R, Ollert M, Spillner E, et al. Detection of IgE to recombinant Api m 1 and rVes v 5 is valuable but not sufficient to distinguish bee from wasp venom allergy. J Allergy Clin Immunol 2011;128:247-8. 7. Golden DB, Moffitt J, Nicklas RA, AAAAI. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. 8. Niedoszytko M, deMonchy J, vanDoormaal JJ, Jassem E, Oude-Elberink JNG. Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy. Allergy 2009;64:1237-45. 9. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105: 385-90.
Question: I have a 60-year-old female patient with a history of venom hypersensitivity, allergic rhinitis, and mild asthma who has taken venom immunotherapy (VIT) at maintenance since 2005. When initially tested in 2003, she had demonstrated 4þ reactivity to wasp and 2þ reactivity to white hornet. She started venom immunotherapy at that time but discontinued them after approximately 9 months because of perceived delayed local reactions (she would complain of a sense of exterior neck swelling, although findings were never visible on examination). She was subsequently stung several times and had progressively worsening reactions, one of which required emergency department evaluation. After that episode, she elected to resume VIT in early 2005 and has tolerated it ever since without problem. She has had at least one sting since resuming VIT (she thinks it had been a wasp) which she tolerated with no symptoms. She wanted to know whether continued immunotherapy for stinging insects was warranted, and the option of updated testing was offered. Because she had been stung several times since the initial testing, the full panel of all stinging insects was completed. She had no change in response to the white hornet, a decreased response to wasp (2þ reactivity), but she now demonstrated 3þ reactivity to yellow jacket, 2þ to yellow hornet, and 1 to 2þ on honeybee (HB). An ImmunoCAP was then obtained, which showed moderate levels all of all stinging insects as follows: HB, 1.02 kUA/L; yellow hornet, 1.44 kUA/L; white hornet, 4.85 kUA/L; and common wasp, 1.73 kUA/L. (Yellow jacket was inadvertently omitted by the laboratory.) Do you think it is advisable to revise her current VIT to reflect these new sensitizations, essentially “restarting” her immunotherapy, or to continue her existing maintenance formula of the wasp and white hornet? She is willing to start over if it is recommended (this was before I had received the results of the serum testing). Thanks very much. Response: This question was posed to Dr. David Golden, MD, who responded as follows.
Conflicts of interest: David Golden has received clinical trial grants from Siemens Diagnostics and ALK-Abello. Available online February 5, 2013. Cite this article as: Lieberman P, Golden D. When to discontinue venom immunotherapy: The role of retesting to venom. J Allergy Clin Immunol: In Practice 2013;1:202-3. http://dx.doi.org/10.1016/j.jaip.2012.12.004. J Allergy Clin Immunol: In Practice 2013;1:202-3. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2012.12.004
202
Although most of our clinical decisions are based on the severity of the reactions to stings, this is a question about the diagnostic methods and the choice of venoms for immunotherapy. There are 3 possible explanations for the observed changes in venom sensitivity. First, the original tests may have missed some sensitivities. Venom skin tests are known to have some variability over time such that one of the venoms could be negative, but repeat tests weeks or months later could be positive (and the converse also occurs).1 So if tests are positive to some but not all venoms, it may be helpful to repeat skin tests or to check serum venom-IgE levels, before finalizing the selection of venoms for VIT. We cannot know at this time whether such additional tests would have showed additional sensitivities. Second, it is possible that the interval stings were from different species and caused neo-sensitization. Third, additional sensitivities could be due to immune responses to an expanded repertoire of antigenic epitopes during VIT.2 RAST inhibition tests could determine whether the vespid sensitivities in this patient are all cross-reactive or whether she has specific and unique sensitivities to multiple species.3 If they are cross-reactive, then her VIT with wasp and white hornet will cross-protect her against yellow jacket and yellow hornet. New sensitization to HB in a 60-year-old is most unlikely unless she gardens without gloves or walks barefoot in the grass. Dual sensitization to vespid and HB venoms is usually due to crossreacting carbohydrate determinants (CCDs). This type of crossreactivity can be distinguished by serologic testing with recombinant venom allergens (which are expressed without the CCD components).4-6 But in the end, unless we can prove in vitro that the new sensitivities are not clinically significant, I must return to my first statement: our clinical decisions are based on the severity of the reactions to stings. This requires more detailed information about the pattern of her reactions. It is not clear whether she had significant hypotension or airway obstruction. If she had such reactions, and they had become progressively more severe, I would be tempted to give her an additional 3 years of VIT with all 5 venoms. I could be persuaded to omit the HB venom if she promises not to garden without gloves or to walk barefoot in the grass. There are also a number of issues that arise in the patient’s original question about how long she needs to continue VIT, and how this question can be best answered. Patients who have had VIT at maintenance doses for 5 years or more are generally able to stop treatment and have about 10% chance of systemic reaction to each subsequent sting, even more than 10 years later, and even if venom skin tests become negative.7 If the patient is stung on several occasions over a period of years, the chance of reaction is increased.
J ALLERGY CLIN IMMUNOL: IN PRACTICE VOLUME 1, NUMBER 2
Almost all these reactions are much milder than the pre-VIT reaction. The chance of a systemic reaction and the chance of a severe reaction are associated with several “high-risk factors.” The chance of relapse (systemic reaction to a subsequent sting) is increased in patients who had systemic reactions during VIT (either to venom injections or to stings), in those with frequent exposure to stings, and in patients with allergy to HB.7 The chance of severe or fatal anaphylaxis is highest in patients with a history of severe (near-fatal) sting reactions or with elevated baseline serum tryptase or mastocytosis.8 The decision whether to stop VIT must take into account several factors. One must review the history of the original sting reaction and of the patient’s VIT for any evidence of high-risk factors. There should be a balanced discussion with the patient about the relative chance of reaction on discontinuing treatment, and how comfortable the patient is with the decision to stop. However, the decision cannot be made any easier by venom-IgE tests (skin or serum), and in fact, the results might complicate the decision as they did in this case. The level of sensitivity is not predictive of outcome, and even patients with negative skin tests have had relapses (even near fatal).9 So my opinion in this case may revolve around the exact nature of her “progressively more severe reactions” before VIT. If she had marked hypotension or respiratory distress, she should not stop VIT. If she had “mild-to-moderate” systemic reactions, and if we assume that her reaction to initial VIT were not true systemic reactions, then she should consider stopping VIT. Ideally, we would also check her baseline serum tryptase. Because her treatment included both Vespula and Polistes species, I feel the “new” vespid sensitivities are probably cross-reactive.
ASK THE EXPERT
203
Please understand that I can only express opinions that are based on the available information about the patient. Any recommendation specific for this patient must be based on the clinical judgment of the allergist who has directly evaluated the patient and had a personal discussion with the patient. REFERENCES 1. Graif Y, Confino-Cohen R, Goldberg A. Reproducibility of skin testing and serum venom-specific IgE in Hymenoptera venom allergy. Ann Allergy 2006;96:24-9. 2. Tavares B, Rodrigues F, Pereira C, Loureiro G, Chieira C. Development of new IgE specificities to hymenoptera allergens during venom-specific immunotherapy. Eur Ann Allergy Clin Immunol 2005;37:171-6. 3. Hamilton RH, Wisenauer JA, Golden DB, Valentine MD, Adkinson NF Jr. Selection of Hymenoptera venoms for immunotherapy based on patients’ IgE antibody cross-reactivity. J Allergy Clin Immunol 1993;92:651-9. 4. Muller UR, Johansen N, Petersen AB, Fromberg-Nielsen J, Haeberli G. Hymenoptera venom allergy: analysis of double positivity to honey bee and Vespula venom by estimation of IgE antibodies to species-specific major allergens Api m1 and Ves v5. Allergy 2008;64:543-8. 5. Eberlein B, Krischan L, Darsow U, Ollert M. Double positivity to bee and wasp venom: improved diagnostic procedure by recombinant allergen-based IgE testing and basophil activation test including data about cross-reactive carbohydrate determinants. J Allergy Clin Immunol 2012;130:155-61. 6. Sturm GJ, Hemmer W, Hawranek T, Lang R, Ollert M, Spillner E, et al. Detection of IgE to recombinant Api m 1 and rVes v 5 is valuable but not sufficient to distinguish bee from wasp venom allergy. J Allergy Clin Immunol 2011;128:247-8. 7. Golden DB, Moffitt J, Nicklas RA, AAAAI. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. 8. Niedoszytko M, deMonchy J, vanDoormaal JJ, Jassem E, Oude-Elberink JNG. Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy. Allergy 2009;64:1237-45. 9. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105: 385-90.
