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.)