Insect Sting Allergy and Venom Immunotherapy David B.K. Golden, M.D. Johns Hopkins University, Baltimore History of Reaction to Insect Stings (Skin Test Positive Patients) No reaction Large Local Cutaneous Systemic Anaphylaxis INSEC T ALLERGY CASE 1 A 32 yea r old man with a his tory of seve re and prolonged swelling fr om previous insec t stings is stung on the leg. Aft er 15 minu tes he develops gene rali zed hives, swelling of lips and hands, with no throat tigh tness or dizz iness. Symp toms resolve aft er 1 hou r. The nex t day the E.D. tr eats his seve re leg s welling and discha rges him on antibio tics. Severe swelling 24 hrs after a sting should be treated with: A. Antibiotics C. Antihistamine B. Prednisone D. Venom immunotherapy E. Epinephrine INSEC T ALLERGY CASE 1b A 12 yea r old boy on the school cross -coun tr y tr ack team is running in a wooded area when he is stung tw ice on the arm. Within 5 minu tes he develops throat tigh tness follo wed rapidly by gene rali zed hives and angioedema, di zziness and dyspnea. He is helped back to school and met by pa ramedics who adminis ter epineph rine and tr anspo rt him to the emergency depa rtment for prolonged obse rva tion. Venom immunotherapy: A. Is not necessary (“He’ll outgrow it”) B. Is dangerous C. is only partially effective E. None of the above D. Is forever Diagnosis of Insect Sting Allergy (Indications for Venom Immunotherapy) • History • Venom Skin Test (RAST) • Natural History Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children Frequency (%) Symptoms or Sign Adults Children Cutaneous only 15 60 Urticaria/angioedema 80 95 Dizziness/hypotension 60 10 Dyspnea/wheezing 50 40 Throat tightness/ Hoarseness 40 40 Loss of consciousness 30 5 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. Correlation of Yellow Jacket Venom RAST and Skin Tests (Golden - JAMA 1989) RAST (ng/L) < 1 (negative) ≥ 1 (positive) 1.0 - 1.9 2.0 - 2.9 3.0 - 4.9 ≥5.0 Total Venom Skin Test Positive Negative 9 (24%) 190 (89%) 29 (76%) 23 (11%) 8 5 4 12 9 4 5 5 38 213 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 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%) Venom Skin Test / RAST in History Positive Patients (Golden - JACI 2001) Total history positive patients screened: ST positive 208 (68%) ST negative 99 (32%) ST - neg/RAST neg 56 (57%) ST - neg/RAST positive 43 (43%) RAST 1 - 3 ng/ml RAST 7 - 243 ng/ml 36 7 (N=307) (18%) Diagnosis of Insect Allergy in Patients With Positive History (Systemic) Skin test positive 68% ST negative / RAST positive 14% ST neg / RAST neg / sting challenge positive No sting allergy 1% 17% Low Risk Sub-Groups of Patients With Positive Venom Skin Tests Sting Reaction History Children - Cutaneous Systemic Large Local Risk of Systemic Reaction 10 % 5 - 10 % Insect Sting Allergy in Children (1978 -1987) (Schuberth, Valentine, Kagey-Sobotka, Lichtenstein) History N Disposition of Patients Cutaneous systemic 462 Untreated vs. VIT • untreated (n=352) • treated (VIT) (n=110) Mod-severe systemic 345 VIT advised • untreated • treated (VIT) Large Local 226 TOTAL 1033 No VIT (n=99) (n=246) Summary Of Sting Reactions 490 Stings in 180 Patients over 9 Yrs 100% 90% 80% 0.4% 10 % 25% 70% 60% 50% 40% 30% 20% 10% 0% 65% Severe SR Mild SR Large Local Normal Natural History of Large Local Reactions Diagnostic Test Skin Test RAST Sting Reaction Systemic LL Graft et al (J Ped 1984) children 105/125 (84%) 2/54 (4%) 20/54 (37%) 1/28 (4%) 21/28 (75%) Mauriello et al 105/133 adults and children (79%) (JACI 1984) 67/133 (50%) Golden et al (JACI 1984) adults 38/52 (73%) 5/52 (10%) Abrecht et al (Clin Allergy 1980) children and adults 27/40 (68%) 29/40 (73%) 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%) 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 systemic Child Adult 10 % 20 % 5% 10 % Anaphylaxis Child Adult 40 % 60 % 30 % 40 % INSEC T ALLER GY CASE HISTORY A 28 yea r old man was stung by a yello w jacket and rapidly developed gene ralized hives, dyspnea and th roat tightness, follo wed by seve re dizziness with nea r-unconsciousness. He responded well to eme rgency medical treatment. He was discha rged with no specific recommendation except fo r a presc ription fo r an epineph rine injection device. He presents to the alle rgist because his uncle died from insect sting alle rgy and his family and docto rs have told him the next sting will su rely kill him. Pr evious stings had caused no abno rmal reaction. Controlled Trial of Venom Immunotherapy (Hunt et al, NEJM 1978) Trea tment Stung S ystem ic (%) Venom (n=19) 18 1 (5%)* W B E (n=20) 11 7 (64%) Placebo (n=20) 12 7 (58%) * afte r crossover, tota l 1/55 = 2% on VI T (p<0.01 ) Venom Immunotherapy Treatment Protocols Conservative Regimen Weeks to Mc Dose (µg) Maintenance (wks) Traditional 20 - 26 Moderate Modified Rush Liberal Rush 8 1 50 100 200 4 6-8 12 Dose Response of Venom Immunotherapy (Rueff et al JACI 2001;108:1027-32.) Premedication During Venom Immunotherapy Terfenadine Placebo Brockow et al (JACI 1997) Systemic during VIT 1/82 (1%) 6/39 (15%) 20/80 (24%) 17/39 (45%) Systemic during VIT 5/24 (21%) 13/23 (56%) Systemic to challenge sting 0/20 Large Local during VIT Muller et al (JACI 2001) 6/21 (28%) Venom-IgE and Skin Test During and After Venom Immunotherapy 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. Discontinuing Venom Immunotherapy (Lerch and Muller 1998) N (pts/stings) Systemic Reaction (%) P VIT Duration <50 months >50 months 118 pts 82 pts 21 (18%) 4 (5%) 0.007 Insect Honeybee Vespid 120 pts 80 pts 19 (15.6%) 6 (7.5%) 0.08 Time since D/C VIT 1-2 years 3-5 years 6-7 years 444 stings 211 stings 64 stings 20 (4.5%) 30 (14%) 5 (8%) 0.001 Discontinuing Venom Immunotherapy (Golden et al JACI 2000) Systemic reaction Venom Skin Test Positive 10% / sting Venom Skin Test Negative 10% / sting Off VIT 3 yrs (1 - 4 yrs) 10% / sting Off VIT 10 yrs (5 - 13 yrs) 10% / sting Cumulative risk (10 yrs) 17% 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.)