1. Insect Sting Allergy and Venom Immunotherapy David B.K. Golden, M.D. Johns Hopkins University, Baltimore

2. History of Reaction to Insect Stings (Skin Test Positive Patients) No reaction Large Local Cutaneous Systemic Anaphylaxis

3. Severe swelling 24 hrs after a sting should be treated with: A. Antibiotics C. Antihistamine E. Epinephrine B. Prednisone D. Venom immunotherapy

4. Venom immunotherapy: A. Is not necessary (“He’ll outgrow it”) B. Is dangerous C. is only partially effective D. Is forever E. None of the above

5. Diagnosis of Insect Sting Allergy (Indications for Venom Immunotherapy) History Venom Skin Test (RAST) Natural History

6. Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children Frequency (%) Symptoms or Sign Adults Children Cutaneous only 1560 Urticaria/angioedema8095 Dizziness/hypotension6010 Dyspnea/wheezing5040 Throat tightness/4040 Hoarseness Loss of consciousness30 5

7. Epidemiology of Venom Allergy History of systemic reaction in 0.5%-3.0% of the population Positive venom skin test or RAST in 15%-25% of the population. Transient positive skin test or RAST may occur after uneventful sting. Presence of IgE venom antibody not necessarily predictive of clinical reactivity.

8. Correlation of Yellow Jacket Venom RAST and Skin Tests (Golden - JAMA 1989) Venom Skin Test RAST (ng/L) Positive Negative < 1 (negative) 9 (24%) 190 (89%) ≥ 1 (positive) 29 (76%) 23 (11%) 1.0 - 1.9 8 9 2.0 - 2.9 5 4 3.0 - 4.9 4 5 ≥5.0 12 5 Total 38 213

9. History Positive Patients with Negative Venom Skin Tests Possible explanations: Not true allergic reaction (no objective signs) Allergy “outgrown” Mastocytosis (~1 % of insect allergic patients) Not detected: - Refractory period (anergy) - RAST positive

10. Diagnostic Venom Test Reactivity after Systemic Sting Reaction (Goldberg and Confino-Cohen; JACI 1997) Time after sting 1 week 4 - 6 week Any Skin Test Positive 20 (53%) 15 (39%) 35 (92%) RAST Positive 24 (63%) 8 (21%) 32 (84%) Any Positive 30 (79%) 8 (21%) 38 (100%)

11. Venom Skin Test / RAST in History Positive Patients (Golden - JACI 2001) Total history positive patients screened: (N=307) ST positive 208 (68%) ST negative 99 (32%) ST - neg/RAST neg 56 (57%) (18%) ST - neg/RAST positive 43 (43%) RAST 1 - 3 ng/ml 36 RAST 7 - 243 ng/ml 7

12. Diagnosis of Insect Allergy in Patients With Positive History (Systemic) Skin test positive68% ST negative / RAST positive14% ST neg / RAST neg / sting challenge positive 1% No sting allergy17%

13. Low Risk Sub-Groups of Patients With Positive Venom Skin Tests Risk of Sting Reaction History Systemic Reaction Children - Cutaneous Systemic 10 % Large Local 5 - 10 %

14. Insect Sting Allergy in Children (1978 -1987) (Schuberth, Valentine, Kagey-Sobotka, Lichtenstein) History N Disposition of Patients Cutaneous 462 Untreated vs. VIT systemic untreated (n=352) treated (VIT) (n=110) Mod-severe 345 VIT advised systemic untreated (n=99) treated (VIT) (n=246) Large Local 226 No VIT TOTAL 1033

15. Summary Of Sting Reactions 490 Stings in 180 Patients over 9 Yrs

16. Natural History of Large Local Reactions Diagnostic Test Sting Reaction Skin Test RAST Systemic LL Graft et al (J Ped 1984) 105/125 2/54 20/54 children (84%) (4%) (37%) Mauriello et al (JACI 1984) 105/133 67/133 1/28 21/28 adults and children (79%) (50%) (4%) (75%) Golden et al (JACI 1984) 38/52 5/52 adults (73%) (10%) Abrecht et al (Clin Allergy 1980) 27/40 29/40 children and adults (68%) (73%)

17. Repeat Systemic Reaction In Sting Allergic Patients STUDY (YEAR) N SYSTEMIC (%) GOLDEN (1981) 115 75 (65%) HUNT (1978) 23 19 (61%) SETTIPANE (1979) 119 72 (61%) LANTNER (1989) 18 11 (61%) REISMAN (1992) 220 124 (56%) GALATAS (1994) 27 13 (48%) PARKER (1982) 16 7 (44%) DVORIN (1984) 19 8 (42%) BLAAUW (1985) 86 29 (39%) FRANKEN (1994) 228 90 (39%) vanderLINDEN (1994) 324 96 (30%) TOTAL 1195 544 (46%)

18. Risk of Systemic Reaction in Untreated Skin Test Positive Patients Original Sting Reaction Risk of Systemic Reaction Severity Age 1 - 9 yrs 10 - 20 yrs No reaction Adult 17 % Large local All 10 % 10 % Cutaneous Child 10 % 5 % systemic Adult 20 % 10 % Anaphylaxis Child 40 % 30 % Adult 60 % 40 %

20. Controlled Trial of Venom Immunotherapy (Hunt et al, NEJM 1978)

21. Venom Immunotherapy Treatment Protocols ConservativeModerateLiberal Regimen Traditional Modified Rush Rush Weeks to Mc 20 - 26 8 1 Dose (µg) 50 100 200 Maintenance (wks) 4 6 - 8 12

22. Dose Response of Venom Immunotherapy (Rueff et al JACI 2001;108:1027-32.)

23. Premedication During Venom Immunotherapy Terfenadine Placebo Brockow et al (JACI 1997) Systemic during VIT 1/82 (1%) 6/39 (15%) Large Local during VIT20/80 (24%) 17/39 (45%) Muller et al (JACI 2001) Systemic during VIT 5/24 (21%) 13/23 (56%) Systemic to challenge sting 0/20 6/21 (28%)

24. Venom-IgE and Skin Test During and After Venom Immunotherapy

25. Discontinuing Venom Immunotherapy: Reported Studies and Criteria Author Patients Criteria Studied Proposed Graft (1984) children 5-7 years* 5 years Urbanek (1985) children RAST neg RAST neg Randolph (1986) adults & children RAST neg RAST neg Keating (1991) adults & children 2-10 years* 5 years Haugaard (1991) adults 3-7 years* 3 years Muller (1991) adults & children 3-10 years* 3 years* Reisman (1993) adults & children 1-6 years 3+ years Lerch (1998) adults & children 3-10 years* 5 years # Golden (1998) adults 5-7 years 5 years # * Negative sting challenge included as criterion for discontinuation. # Excluding patients with life-threatening history, honeybee allergy or systemic reaction during VIT.

26. Discontinuing Venom Immunotherapy (Lerch and Muller 1998) NSystemic P (pts/stings)Reaction (%) VIT Duration <50 months118 pts21 (18%) >50 months 82 pts 4 (5%) 0.007 Insect Honeybee120 pts19 (15.6%) Vespid 80 pts 6 (7.5%) 0.08 Time since D/C VIT 1-2 years444 stings20 (4.5%) 3-5 years211 stings30 (14%) 0.001 6-7 years 64 stings 5 (8%)

27. Discontinuing Venom Immunotherapy (Golden et al JACI 2000) Systemic reaction Venom Skin Test Positive10% / sting Venom Skin Test Negative10% / sting Off VIT 3 yrs (1 - 4 yrs)10% / sting Off VIT 10 yrs (5 - 13 yrs)10% / sting Cumulative risk (10 yrs)17%

28. COLLABORATORS Lawrence M. Lichtenstein Anne Kagey-Sobotka Robert G. Hamilton Philip S. Norman Timothy J. Craig Denise C. Kelly Kristin Chichester Tina D. Grace General Clinical Research Center (GCRC): Johns Hopkins Bayview, Baltimore, MD Penn State University, Hershey, PA Funding: NIH AI08270 (L. M. Lichtenstein, P.I.)