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 from 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 dizziness. Symp toms resolve

after 1 hou r. The nex t day the E.D. treats 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 E. Epinephrine

B. Prednisone D. Venom immunotherapy

INSECT ALLERGY CASE 1b

A 12 yea r old boy on the school cross -coun try track

team is running in a wooded area when he is stung

twice 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 rvation.

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

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/ 40 40Hoarseness

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)

Venom Skin TestRAST (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

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: (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

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 1%

No sting allergy 17%

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 %

Insect Sting Allergy in Children (1978 -1987)(Schuberth, Valentine, Kagey-Sobotka, Lichtenstein)

History N Disposition of Patients

Cutaneous 462 Untreated vs. VITsystemic • untreated (n=352)

• treated (VIT) (n=110)

Mod-severe 345 VIT advisedsystemic • untreated (n=99)

• treated (VIT) (n=246)

Large Local 226 No VIT

TOTAL 1033

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

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Severe SRMild SRLarge LocalNormal

0.4%

10 %

25%

65%

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%)

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 Child 10 % 5 % systemic Adult 20 % 10 %

Anaphylaxis Child 40 % 30 % Adult 60 % 40 %

INSEC T ALLERGY CASE HISTORY

A 28 yea r old man was stung by a yello w jacket and

rapidly developed gene ralized hives, dyspnea and

throat 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 for a

presc ription for 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 surely kill him.

Previous stings had caused no abno rmal reaction.

Trea tment Stung System 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 )

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

Venom Immunotherapy Treatment Protocols

Conservative Moderate Liberal

Regimen Traditional Modified Rush Rush

Weeks to Mc 20 - 26 8 1

Dose (µg) 50 100 200

Maintenance (wks) 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%)

Large Local during VIT 20/80 (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%)

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 Systemic P (pts/stings) Reaction (%)

VIT Duration <50 months 118 pts 21 (18%) >50 months 82 pts 4 (5%) 0.007

Insect Honeybee 120 pts 19 (15.6%) Vespid 80 pts 6 (7.5%) 0.08

Time since D/C VIT 1-2 years 444 stings 20 (4.5%) 3-5 years 211 stings 30 (14%) 0.001 6-7 years 64 stings 5 (8%)

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. LichtensteinAnne Kagey-Sobotka Robert G. HamiltonPhilip S. Norman Timothy J. CraigDenise C. KellyKristin ChichesterTina D. Grace

General Clinical Research Center (GCRC):Johns Hopkins Bayview, Baltimore, MDPenn State University, Hershey, PA

Funding: NIH AI08270 (L. M. Lichtenstein, P.I.)