Hymenoptera venom hypersensitivity 2020

HYMENOPTHERA VENOM ALLERGY
(FOCUSED ON APIDAE & VESPIDAE)
17th July 2020
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit, King Chulalongkorn Memorial Hospital

OUTLINE
• Epidemiology
•Taxonomy
• Insect venom
• Clinical features
• Evaluation & Diagnosis
•Treatment and Prevention
• Predictors of risk for sting anaphylaxis
•Venom immunotherapy

EPIDEMIOLOGY
 56-94% of adults worldwide have been stung a least once in their lifetime
 The prevalence of Systemic reaction :Adult 0.5 - 3.3% in US
Adult 0.3% to 8.9% (Pediatric 0.15% to 0.8%) in European
 The prevalence of large local reaction : 5 to 26.4% for adult and children
 Insect allergy in Thailand: 1.38%
 15.3% had a large local reaction
 15.4% had a mild to moderate systemic reaction
 1.6% had a severe systemic reaction
 The positive rate of sensitization to honey bee 0.9% mixed wasp 1.8%
yellow hornet 5.5% fire ant were 33.9%
Journal of Medicine and Health Sciences.2014; 21:32-39
J Investig Allergol Clin Immunol 2019; Vol. 29(3): 180-205

TAXONOMY
Helbling Ulrich R.Müller et al. Allergic Reactions to Stinging and Biting Insects .Clinical Immunology (5th Edition) ,2019, Pages 601-610.e1
Honey bee Bumble bee
Hornet
Paper wasp
Fire ant
Yellow jacket
White faced hornet
Yellow hornet Jack jumper
ant
Harvester
ant
ไม่พบในประเทศไทย

David B K Golden. Insect allergy .Middleton’s allergy 9th edition .2020

APIDAE
Honey bee (Apis mellifera)
-Lose sting when stinging → sting
one times and die
- Most stings occur in summer and
fall, spring
- rarely sting or swarm without
considerable provocation,
- Mostly in defense of their nest and
queen
- Nest : natural hollows
Bumble bee (Bombus terrestris)
- Larger than honey bees, more hairy
-Yellow or white bands on abdomen
- not aggressive
- uncommon causes of sting reactions
-Very limited cross reactivity with
honeybee sting reactions
- Able to sting several time
(not die after stinging)
Africanized honeybee (Killer bees)
(Apis mellifera scutellata)
- Similar appearance of honeybee
- tendency to swarm & sting in
large numbers
- Very limited cross reactivity with
honeybee
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 118 (2017) 28e54 Pediatric Allergy & Primary Immunodeficiency Diseases
1st edition 2012

Family Scientific name Common name Thai name
Apidae (Apinae) Apis dorsata Giant bee ผึ้งหลวง
Apis cerana Indian bee ผึ้งโพรง
Apis florea Small bee ผึ้งมิ้ม
Apis andreniformis Black dwarf honey bee ผึ้งมิ้มเล็ก ,ผึ้งม้าน
Apis mellifera Honey bee ผึ้งพันธุ์ต่างประเทศ
Bombus species Bumble bee ผึ้งหึ่ง
Apis florea : ผึ้งมิ้ม
Black dwarf honey bee
Apis cerana
Apis dorsata
Apis mellifera
Bumble bee

VESPIDAE
 Construct nests by wood pulp and enclosed in papier-mache outer layers
 Sting apparatus usually has finer barbs than in the apids
 Not commonly autotomize, and able to sting repeatedly
Family: Vespidae
• Vespinae
• Vespula spp.: yellow jacket
• Dolichovespula: yellow hornet, white-faced hornet
• Vespa: european hornet
• Polistinae: paper wasp
• Not Lose sting when stinging → sting several times
• Most stings occur in summer and fall
• Extensive cross-allergenicity of different genera***

Vespidae
(Subfamily :
Vespinae)
Vespa tropica Tropical hornet ต่อหลุม ,ต่อหัวเสือแถบใหญ่
Vespa affinis Tropical hornet ต่อหัวเสือบ้าน
Vespa basalis ต่อหัวเสือดา
Vespa binghami ต่อหัวเสือบิงแฮม
Vespa velutina ต่อหัวเสือดอย
Vespa bicolor ต่อหัวเสือเหลือง
Vespa mandarinia ต่อหัวเสือยักษ์
Vespa mocsaryana ต่อหัวเสือปักษ์ใต้
Vespa multimaculata ต่อหัวเสือปากลาย
Provespa barthelemyi ต่อนอนวันธรรมดา
Provespa anomala ต่อนอนวันเล็ก
Vespulaspecies Yellow jacket ไม่พบในประเทศไทย
Dolichovespula
maculata
White faced hornet ไม่พบในประเทศไทย
Dolichovespula arenaria Yellow hornet ไม่พบในประเทศไทย
Vespidae
( Subfamily :
Polistinae )
Polistes sagitharius Paper wasp ต่อกระดาษ ,แตน
Polistes stigma ต่อฝักบัว
Polistes fasgatus ต่อท้องยาว ,แตน
Vespidae
( Subfamily :
Eustenogaster nigra Hover wasp ไม่พบในประเทศไทย
White faced hornet
Yellow hornet
Yellow jacket
Paper wasp
Provespa barthelemyi
Provespa anomala
Vespa affinis
Vespa tropica
Family
Vespidae

VESPIDAE
Yellow jacket
- Scarvengers:seek their food at picnics and
in orchards,trashcans,and dumpsters
- Highly aggressive and sting for no apparent
reason, particularly in
- Nests are located in the ground or in the
cracks in buildings or residential landscape
Materials
- Not found in Thailand
• Waxy smooth body, 2 pairs of wings
• Wasps in Europe /yellow jackets in the US
• Most aggressive genus
• Nest: ground, in attics, or in shelters
• Ingest sweet/grilled/leftover food, fruit in garbage

VESPIDAE
Yellow hornets and white faced hornets
- Aerial nesting yellow jackets that are present
in North America but not in Europe
- Often build their nests in shrubs and trees
- Their sensitivity to vibration can initiate
Their defensive sting behavior

VESPA
Vespa (Hornet) Provespa
• European hornet
• Much larger size than other vespids
• Hornet stings are rare (exclusively in the vicinity of
nests)
• Nest: hollow trees
• Typically fly at night, attracted to bright lights
• Gradually increasing population, but still minor
stinging threats
• Attracted to bright lights
• Ingest small insects
• Less aggressive, only defense
VespaTropica
Vespa affinis

VESPIDAE
Paper wasps (Polistinea)
- Nests are often found on the eaves or
window-sills of a home and on the railings
of wood decks
- Wasps are recognizable by the narrow
wasp waist and their characteristic
dangling legs when in flight
• Variable coloring
• Less aggressive than yellow jackets and hornets
• Nest: single layer of open cells (i.e., comb)
• Minimal outer covering

FORMICIDAE
 Imported fire ant: Solenopsis invicta (red), Solenopsis richteri (black)
 Nests in mounds composed of freshly disturbed soil
 Very aggressive, particularly if their nests are disturbed, and are
often responsible for multiple stings
 When they bites, they anchor by their mandibles and pivot to
administer multiple stings
 The unique lesions form sterile pustules that can become infected if
excoriated or opened
Solenopsis invicta
Solenopsis richteri

FORMICINAE (ANT)
 True sting apparatus: mandible and sting at abdomen
 Multiple stings: sting in half circle area
 Nest: ground, house, buildings
 Not painful , unique lesions form sterile pustules after 24 hr
 Alkaloid → tissue injury → Possible infect if excoriated
 No cross-allergenicity of different genera***
 Significant cross-reactivity among the various fire ant (Solenopsis) species and among
the harvester ant (Pogonomyrmex) species***

Formicidae
(Myrmicinae)
Solenopsis invicta Fire ant ไม่พบในประเทศไทย
Solenopsis richteri ไม่พบในประเทศไทย
Solenopsis geminata มดคันไฟ
Formicidae (Ponerinae) Tetraponera rufonigra มดตะนอยอกส้ม
Pachycondyla chinensis มดปุยฝ้ายจั่วจีน
Odontoponera denticulata มดไอ้ชื่นดา
Diacamma rugosum มดหนามคู่สีเทา
Formicidae
(Pseudomyrmecinae)
Solenopsis geminata
มดคันไฟ
Tetraponera rufonigra
มดตะนอยอกส้ม
Pachycondyla chinensis
มดปุยฝ้ายจั่วจีน
Odontoponera denticulata
มดไอ้ชื่นดา

COMPOSITION OF VENOMS
▪ Systemic toxic effect (within 24 hr to 6 days)
• Dose dependent (multiple stings)
• Rhabdomyolysis, intravascular hemolysis,ATN,
myocardial injury, hepatic injury, brain edema,
coagulopathyVenoms
Toxin
Non-immunologic Reaction
-Vasoactive substances
• Amines : Histamine, dopamine, norepinephrine
• Acetylcholine
• Kinins
- Primary protein enzymes
- phospholipase
- Hyaluronidase,
- Apamin (neurotoxin)
- Mellitin ,antigen 5
Allergen
immunologic Reaction
 Major allergen: >50% patient have allergic
 Limited cross-reactivity between honeybee and vespid venoms***
 “Double positive”
 Cross-reacting carbohydrate determinants: uncertain clinical significance
 Bee hyaluronidase: 55% identical sequence to vespid (allergy to bee & vespid)

PHYSICOCHEMICAL AND BIOCHEMICAL CHARACTERISTICS
OF INJECTED ARTHROPOD-DERIVED ALLERGENS
Geoffrey A.Stewart, Clive Robinson. The structure & function of allergen .Middleton’s allergy 9th edition .2020
Phospholipase A2
- Highly potent
- 10- 15% of dry weight of bee venom
- Cytotoxin and indirect cytolysin
Hyaluronidase
-1% of dry weight
- Increases permeability of connective
tissue
Melittin
- major component (50% of dry weight)
- only 28% of patients have specific IgE
ab against this peptide

D.Antolín-Amérigo, et al.: Component-resolved diagnosis in hymenoptera allergy,Allergology and Immunopathology, 2018
Similar Phospholipase A2 of various bee →
significant cross reactivity among Apis spp.
Allergen Name
Apis cerana : Api C1 Phospholipase A2
Api C2 Hyaluronidase
Api C4 Melittin
Apis dorsata : Api d1 Phospholipase A2
Api d4 Melittin
Apis florae : Api fl 4 Melittin
Allergen: Bombus pennsylvanicusAllergen: Other Apis species
Allergen Name
Bom p1 Phospholipase A2
Bom p2 Hyaluronidase
Bom p3 Acid phosphatase
Bom p4 Serine protease
Unique PLA2 of various bumble bee → limited cross
reactivity among bombus spp.

Phospholipase A1 (Ves v1):
- Digests cell membranes
- not related to phospholipaseA2 of bee venom
Antigen5 (Ves v5): most potent
- Neurotoxin to neuromuscular junction
Major
allergen
Minor
allergen
Hyaluronidase (Ves v2)
- Part of the cross-reactivity between
bee and vespid
- Hyaluronidase is due to specific IgE
to carbohydrate epitopes

VESPINAE ALLERGENS
Maria B. Bilo et al.The role of component-resolved diagnosis in Hymenoptera venom allergy . Curr Opin Allergy Clin Immunol ,December 2019, 19:614–622

POLISTINAE ALLERGENS

90–95% alkaloid
- Bactericidal, cytotoxin, hemolysis
- Early wheal and flare and later pustule formation (not allergenic)
Sol i 1 and Sol i 3 are major allergens (1%)
Significant cross-reactivity among various fire ant
(Solenopsis spp.) not cross with other Hymenoptera

FORMICIDAE ALLERGENS

VENOM DOSE
 Hymenoptera deliver between 50 ng (ﬁre ants) and 140 μg (honeybees) of venom
with each sting
 Honeybee : 50 - 140 µg of venom protein
 Bumblebee : 10 - 31 µg of venom protein
 Vespula : 1.7 - 3.1 µg of venom protein
Dolichovespula : 2.4 - 5.0 µg of venom protein
Polistes : 4.2 - 17 µg of venom protein
 Fire ant : 50 ng of venom protein

CROSS REACTIVITY
 True double sensitization
 Cross-reactive IgE antibodies which recognize similar epitopes of different venoms, especially
carbohydrate-containing epitopes of venoms and common allergens
Within family
- Apidae family : Bumblebee venom contains unique allergens and has variable cross-
reactivity with honeybee venom
- Vespidae family : Extensive: in different genus hornet(vespa) - yellow jacket (vespula)
Less extensive: yellow jacket and hornet - wasp
- Formicidae family : Limited cross-reactivity fire ant venom

CROSS REACTIVITY
 Schematic representation of recombinant marker and cross-reactive
allergens of Apis mellifera,Vespula spp.And Polistes dominula

INVITRO CROSS-REACTIVITY OF HYMENOPTERAVENOMS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 118 (2017) 28e54

CROSS-REACTIVE CARBOHYDRATE DETERMINANTS
(CCD)
 Recombinant allergens devoid of cross-reactive carbohydrate determinants often
help to identify the culprit venom in patients with double sensitivity to YJV and HBV.
Cross reactivity honey bee and yellow jacket venom allergens
 Api m 2 Hyaluronidase Ves v 2
 Api m 5 Allergen Dipeptidylpeptidase IV Ves v 3
 Api m 12 Vitellogenin Ves v 6

• Local reaction(LR)
• Large local reaction(LLR)
Clinical features
• Toxic effect : Redness , swelling , itching and pain
• Resolve in few hours (<24hr)
• Solenopsis: pustule , heals after 1-2 week
• Painful swelling and erythema limited to skin and subcutaneous tissues contiguous
with the sting site typically >10 cm , can crossing joint line
• Develop within minute to hours , peak 24-48 hr, subside after 3-10 days
• May cause lymphangitis/lymphadenopathy, fever, malaise
• Complication: local anatomic compression esp. head, neck, tongue or throat
• IgE (80% of patient) or cell mediated mechanism or both
• Restringing → <5% anaphylaxis

Clinical features : systemic reaction
Cutaneous systemic reaction Systemic anaphylactic reaction
-limited to the skin
-widespread and involves skin is not contiguous
with the sting site
-involving angioedema of the tongue or throat,
which could compromise the airway
- The absence of urticaria or angioedema is associated
with more severe reactions to stings.
- Protracted anaphylaxis occurs much less often than
with food allergy.
- Underlying mast cell disorder: 1-2% of cases
- 25% severe anaphylaxis → elevated serum tryptase
Usually IgE mediated > IgG, complement (IgG-venom complex)
Severity : age onset after stinging, number of sting , site of sting esp. head&neck region(high vascular supply)

CLASSIFICATION OF SYSTEMIC REACTION
Allergy. 2005 Nov;60(11):1339-49.

CLASSIFICATION SEVERITY OF ACUTE ALLERGIC REACTIONS
Muraro A, et al. The urgent need for a harmonized severity scoring system for acute allergic reactions. EAACI. Allergy. 2018.

KOUNIS SYNDROME

Clinical features : Unusual reaction
• Rare , unknown mechanism
• After hours to days (> 4 hours) , delay reaction
• Serum sickness like
• Peripheral neuropathy, polyradiculomyelitis, EPS, ADEM
• AGN, AIN
• Vasculitis
• Hemolytic anemia, thrombocytopenia, HSP

RISK FACTOR FOR SEVERE REACTIONSTO STINGS
Bee: high vol of venom → SR 50%
(vespid → SR 25-39%)
> 1.0 kU/L →  systemic reaction 12 X
> 5 ng/ml -> ↑ severe
anaphylaxis
David B.K. Golden et al.Stinging insect hypersensivity: practice parameter update 2016. Ann Allergy Asthma Immunol 118 (2017)
Time interval between stings < 2 months
Less number of stings per year
90% Adults with systemic reaction → severe
70% Children with systemic reaction → mild
Abnormal mast cell mediator

NATURAL HISTORY
 Asymptomatic sensitization: subsequent SR 5-15%
 LLR: subsequent SR 4-10% (7%) in both adult and children
Most have similar reaction after subsequent sting
Beekeepers: ↓LLR if frequent stings
 Cutaneous SR: subsequent SR 10%(<3% more severe reaction)
 SR: subsequent SR 25-75% (severity depend on previous SR)

NATURAL HISTORY

 History of a sting event
Diagnosis
• Identify insect
• Characteristic, nest, number of stings,
provocation to sting, location(near nest)
• Previous insect sting & reaction
• Underlying, current medication
• Differentiate allergic/toxic reaction
• Tell severity
• Predict future reaction
• Vital sign
• Oxygen saturation
• Skin lesion
• Presence of sting
• EKG 12 lead (if clinical suggest)
 Physical examination

DIAGNOSTICTEST
 • InVivo test
- Skin prick test (SPT)
- Intradermal test (ID)
- Sting challenge
 • InVitro test
- sIgE : RAST
- Serum tryptase
- Basophil activation test (BAT)
D.B.K. Golden / Ann Allergy Asthma Immunol 111 (2017) 84-89.
Purpose :
1.) Confirm allergic sensitization
2.) Define the risk of future systemic reaction to stings (Candidates VIT)

 Indication for venom specific IgE
Diagnosis
- 27 - 40 % of adults in the general population
have detectable venom-specific IgE in the serum
- sIgE not sufficient to make the diagnosis of a
venom allergy or predict that the patient is at
elevated risk for a systemic reaction to a future
sting
Testing is not indicated
- Large local reactions
- Cutaneous systemic reaction
- without a sting history
- Asymptomatic sensitization to honey bee and
vespid venoms may be as high as 40 %
- Most patients with venom anaphylaxis have
no family history of venom allergy

 Skin test
Diagnosis : Skin test
- Performed at least 2 weeks after a sting
reaction
- 5 Hymenoptera venom protein extracts
(honey bee, yellow jacket, yellow hornet,
wasp, white face hornet): freeze-dried
venom
- Mixed vespid venom (yellow jacket, yellow
hornet, white faced hornet) → for VIT
Skin prick test : 1-100 μg/mL
Intradermal test : 0.001- 1 μg/mL
- If negative →increase concentration by 10-fold until positive
occurs or max concentration of 1.0 μg/mL is reached (False
positive results have been concentrations >1.0 μg/mL)
- Positive skin test response at concentration ≤ 1.0 μg/mL
demonstrates the presence of specific IgE ab
Fire Ant Hypersensitivity
- Imported fire ant whole-body extract
- Skin prick test : 1: 1000 (wt/vol)
- Intradermal test: 1:106-1:103or 2:103 (wt/vol)
no correlation between the severity of a reaction and
the scores of in vivo and in vitro diagnostic tests

SKIN TEST RECOMMENDATION
Reference SPT IDT Positive result
Middleton 9th edition
(refer จาก EAACI 2005)
1–100 mcg/mL 0.001-1 mcg/mL IDT : wheal ≥ 3 - 5 mm with
surrounding erythema > Negative -
Practice parameter 2016 less than or equal to 1 mcg/mL
demonstrates the presence of
specific IgE antibodies
0.001 -1 mcg/mL, if –ve increased
by 10-fold until positive response
occurs or
maximum 1 mcg/ml
SPT: wheal diameter ≥ 3 mm
IDT : wheal ≥ 3 - 5 mm with
surrounding erythema > Negative
BSACI 2011 1–100 mcg/mL 0.001-1 mcg/mL SPT: wheal diameter ≥ 3 mm
>negative
IDT: bleb of diameter 3–5 mm and
wheal diameter of 3 mm at 20 min
Package insert
(ALK)
1 mcg/ml Start 0.001 mcg/ml เพิ่ม 10 เท่า
until 1 mcg/ml
Wheal >5-10 mm, erythema
>11-20 mm more than negative
control

 Venom specific IgE
- Usually increases within days or weeks after a sting
- In patients with no detectable specific IgE to the presumptive relevant venom, the tests
should be repeated after a few weeks
- Sensitivity lower than IDT
Diagnosis :Venom specific IgE
no correlation between the severity of a reaction and
the scores of in vivo and in vitro diagnostic tests

Skin testing: more sensitive and less expensive
- positive in 66 - 90% of patients with a history suggestive of venom allergy
- Complementary /alternative test
- Negative skin test or unable to do ( Dermatographism , severe skin disease )
- 15 – 20% of patients with positive skin tests → undectable sIgE
- 5 -10% of patients with negative skin tests → positive sIgE (high sensitivity)
• Test all 5 venoms except for definitely known culprit
Diagnosis : comparison of testing method

- Not recommended as a routine diagnosis
- To determine the relapse rate after discontinuation of VIT, efficacy of VIT
Limitation
- 20% of patients who do not react to a sting challenge will react after a second challenge
- Serious allergic reactions have occurred
- Less reliable with vespids than with honey bee
- The variability of the culprit insect
Diagnosis : Sting challenge test

INVESTIGATION : SERUMTRYPTASE
Strong recommendation
If elevate → ↑Severe reaction before/during/postVIT

MASTOCYTOSIS
 2% of patients with insect sting anaphylaxis → mastocytosis
 25% of patients with mastocytosis → insect sting anaphylaxis
 Can present as idiopathic/insect sting anaphylaxis without normal skin test & sIgE
 Most common cause of anaphylaxis
• All mastocytosis patients: test for hymenoptera sensitivity
• Expert opinion: discuss risk&benefit of VIT in test positive with mastocytosis Esp.
if have additional risks for severe reaction
Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy,Allergy 2009

BASOPHIL ACTIVATIONTEST
 Usually conc: 0.1-1 mcg/ml
 Improve sensitivity and specificity from serum sIgE
 Not routinely use
 For Dx and monitor VIT effectiveness
 One study suggested that basophil activation tests can be useful in the setting of negative
intradermal test results to complement sIgE testing when the latter is positive
 Another study suggested basophil activation tests may be useful for aiding the decision to
cease immunotherapy.

COMPONENT RESOLVED DIAGNOSIS (CRD)
 Studied in Europe
 Limited use in USA
 For honey bee
• rApi m 1: sensitivity 57-96%
• Natural Api m : sensitivity 91%
 For yellow jacket
•Ves v 1: sensitivity 84-87%
•Ves v 1+5: sensitivity 92%
•Complimentary diagnostic tool
• Multiple sensitization: cross-reactivity or true multiple
sensitization
- Api m2 vs Ves v2
- Api m12 vs Ves v6
- Api m5 vs Ves v3
• Undetectable sensitization: major allergen better sensitive than
whole body
• CCD Cross-reactivity
- Species specific CCD free allergen: HBV vs YJV protein epitope
homologue

Component-resolved diagnostics (CRD) is a new tool aiming at detecting IgE-mediated sensitizations
against individual, relevant allergens.
CRD is undoubtedly an innovative diagnostic method that leads to a more precise definition of the
sensitization profile of the HVA patient

Thilo Jakob et al .Current Allergy and Asthma Reports (2020) 20:48
: Api m 10 (icarapin) : major allergen of honeybee venom (HBV) with potentially high
relevance for diagnostics and therapy of venom allergy and potential implications for venom-
specific immunotherapy (VIT).
: Api m 10 is a major allergen of low abundance in HBV, unstable protein of unknown function
that exhibits homologs in other insect species.
: 35 to 72% of HBV-allergic patients show relevant sensitization to this allergen. Api m 10 is a
marker allergen for HBV sensitization, which in many cases can help to identify primary
sensitization to HBV and cross-reactivity.
: Api m 10 might support personalized risk stratification in VIT, as dominant sensitization to
Api m 10 has been identified as risk factor for treatment failure. (odds ratio 8.44) , strongly
underrepresented in some therapeutic preparations commonly used for VIT.

- Api m 10 is an apparently unstable allergen of low
abundance in HBV
- Underrepresented in comparison with freshly
prepared crude HBV
- rapid Api m 10 degradation can be slowed down by
addition of human serum albumin,

- Predominant sensitization to Api m 10 (defined as > 50% of sIgE to HBV) prior to the initiation of VIT
represents a relevant risk factor for treatment failure (according to sting challenge tests) with an odds
ratio of 8.44.
- HBV VIT only induced minimal IgG4 to low abundance allergens (Api m 10) while substantial IgG4
induction to high abundance allergens (Api m 1 and Api m 4)
- Suggest patients with dominant Api m 10 sensitization are at increased risk for treatment failure during
honeybee VIT and preferably should be treated with a venom preparation contains amounts of Api m
10 detectable by Western blot.

• Degree ≠ severity
• Degree α frequency
• Good predictor for likelihood of any SR
• All potentially relevant insect or single culprit(if definitely known)
With clear Hx of SR
• If initial test negative → further test(in vitro test, repeat skin test, or both) and basal
tryptase
• If some are negative → further test for negative venom
• If negative after repeat → do not fully R/O (DDx non IgE anaphylaxis, mastocytosis)
Skin Test and InVitro Test
Time to Perform
• At 1 week after sting: sensitivity 79%
• At 1 week and 4-6 weeks after sting: additional 21%
• First few weeks after reaction: may cause false negative due to
refractory (anergy)

Treatment
􀶵 Local reaction
􀶵 Large local reaction
􀶵 Systemic reaction
- Oral prednisone 40 - 60 mg OD or rapidly tapered 2-5 days : reduce significant swelling
- A tetanus booster is not necessary
- Infection is suspected when redness, swelling, and pain become dramatically
worse 3-5 days after the sting
-Acute management of anaphylaxis
- Discharge care
- An anaphylaxis emergency action plan
- Epinephrine autoinjector
- Risk of recurrence should be clearly described
Cold compression ,Antihistamine

Treatment
Treatment (Long term)
• Epinephrine autoinjector
• For Hx of anaphylaxis, LLR+other risks factor (CVS, ↑sting risk) or pt.prefer
• discontinued VIT but present risk factor
• Elevate serum tryptase or mast cell disorder with Hx of systemic reaction
• Medical identification bracelet
• Refer for allergist (in case of severe allergic reaction)
• Consider VIT
• Preventive management

VIT INDICATION
• Anaphylactic reaction + specific IgE to venom allergen (Strong Recommendation;A
evidence)
• Avoid VIT based solely on in vivo and in vitro testing for venom IgE, without a history
of systemic reaction to a sting. (Strong Recommendation; A evidence)

VENOM IMMUNOTHERAPY
Front Immunol. 2019 Aug 21;10:1959.
IL10

VENOM IMMUNOTHERAPY
J Asthma Allergy. 2015 Jul 23;8:75-86

CRITERIA FOR IMMUNOTHERAPY
 History of sting anaphylaxis + positive venom skin test or elevated serum levels of venom-sIgE
 History of large local reaction, cutaneous systemic reaction : VIT not required
 Relevant potential risk factors for a poor outcome following a future sting
- concomitant cardiovascular disease
- use of certain ACE inhibitors or beta-blockers
- abnormal basal tryptase level
- a greater probability of future stings
Bilò MB, et al..J Investig Allergol Clin Immunol 2019; Vol. 29(3): 180-205

VIT RECOMMENDATIONS
Indication /duration LifelongVIT
BSACI 2011 Anaphylaxis or adult with cutaneous
systemic reaction + sIgE or skin test
positive
•Duration 3 years
• DuringVIT → Still has reaction
• AfterVIT → Continue risk of multiple stings
• Elevated baseline tryptase or mastocytosis
EAACI 2018 • Adults and children with moderate-to-
severe allergic reactions
• Adult with systemic sting reactions
confined to generalized skin symptoms if
QoL is impaired
- Duration 5 years
Recommended in major risks for relapse
• Bee venom allergy with frequent unavoidable exposure
•Very severe initial reactions (Muller grade IV or grade III-IV
according to Ring & Messmer)
• Systemic side-effects duringVIT
H1 antihistamine: ↓LLR and mild systemic reaction (not
anaphylaxis)
• Epinephrine autoinjector during and afterVIT
2016
Practice
parameter
- All patients who have anaphylactic
reaction to insect sting and who have
specific IgE to venom allergens
-Duration 3-5 years (prefer 5 years)
• history of severe anaphylaxis
• elevated basal serum tryptase
• systemic reactions duringVIT
• frequently or unavoidable stung

Boyle R.J. et al.Cochrane Database of Systematic Reviews 2012
- 6 randomized controlled trials and 1 quasi‐randomized controlled trial for
inclusion in the review; the total number of participants was 392.
- Ant, bee, and wasp immunotherapy in children or adults with previous systemic
or large local reactions to a sting
- VIT is effective for preventing systemic allergic reaction to an insect sting

Boyle R.J. et al.Cochrane Database of Systematic Reviews 2012

VIT EFFICACY
• Untreatment with VIT : 60% subsequent SR
• VIT: 2.7 % subsequent SR
• Honeybee efficacy: 77-84%
• Vespid efficacy: 91-96 %
• Also effective in delayed anaphylaxis
• Less severity than pre-VIT

RISK FACTORS FOR REDUCED EFFECTIVENESS OFVENOM
IMMUNOTHERAPY (VIT)

SLIT
 An observational study of bee venom SLIT suggested reduced LLR in the majority of
patients treated
 A single RCT of SLIT VIT was identified in the Cochrane review: there was no
evidence that SLIT was less effective than SCIT for reducing risk of SR or LLR in that
review
Cochrane Database Syst Rev. 2012

PROCEDURE OFVIT
• Selection of venom
• Dosage schedules
• Adverse effects
• Special circumstances
• Pregnancy
• Medication
Selection of venom
•Single for culprit (even other multiple positive tests)
•All positive results:
• Radioallergoabsorbent inhibition test: cross reactivity or true dual sensitivity
• CRD to differentiate cross reactivity of allergen or carbohydrate portion
Curr Opin Allergy Clin Immunol 2019, 19:456–461
- EAACI guideline recommends
single venom for treatment in the majority of patients
two different types of insects in which case two venoms
- US guidelines recommend VIT with all venoms giving a positive IgE test.

PROCEDURE OFVIT
• Selection of venom
• Dosage schedules
• Adverse effects
• Special circumstances
• Pregnancy
• Medication
Dosage Schedules
• Initial dose: up to 1 mcg (0.001-0.1 mcg)
• Buildup dose schedule
• Conventional: to maintenance in 4 months
• Modified rush: to maintenance in 8 weeks
• Rush: to maintenance in 2-3 days
• Ultrarush: to maintenance in in 4-6 hr → SR 0-28%
• Maintenance: at least 100 mcg of each venom (50 mcg for child) or
300 mcg for mixed vespid
• Honeybee sting = 50 mcg/sting , Fireant 1:100 wt/vol 0.5 ml
- Duration 12-18 mo → q 4 week then q 6-8 week ,if > 4 years → q 12 weeks
risk of SR (5-10%)

EXAMPLE CONVENTIONAL DOSING
FORVENOM IMMUNOTHERAPY
Hollister-Stier venom extracts
ALK-Abelló venom extracts

EXAMPLE CONVENTIONAL DOSING
FOR FIRE ANT IMMUNOTHERAPY
 Solenopsis invicta or a Mixture of S.invicta and Solenopsis richteri Whole-Body Extract

SYSTEMIC REACTION DURING VIT
ADVERSE EFFECTAND SAFETY
 Stung by the same insect (VIT failure; < 5% esp. honeybee VIT)
 If maintenance at 100 mcg → ↑ dose up to 200 mcg Stung by unknown insect Test to identify
insect (the same or new)
 Systemic reaction
- Approximately 3 – 12% of patients have treatment-induced systemic reactions
- Honey bee venom > yellow jacket venom
- Severe or repeated systemic reactions to injections
- Underlying mast cell disease

ADVERSE EFFECTS
 SR 12-16%
• Adjust dose and schedule
• Rush with premedication: if repeated SR
despite adjust dose and schedule
 *SR usually occur when starting new
vial/lot/manufacturer
Rx : Reduce dose 20-50% or start with caution
 *SR toVIT is not significant affected by BBs,ACEI
(conflicting evidence)
 *Carry epinephrine autoinjector in high risk of SR
LLR
• Not related to risk of anaphylaxis
• Antihistamine in buildup phase: ↓LLR and mild systemic
reaction (not anaphylaxis)
• Montelukast premed (one report: ↓Local reaction)
*Use or avoid antihistamine consistently (easy to assess)
*Antihistamine improve VIT efficacy
Serum sickness like
• Subsided and not prevent maintenance in most pt.
• Not known whether it is related to risk of anaphylaxis

VIT DURATION
• Advice continue injection for 3-5 years
• Extended time or indefinitely in pt with high risk factor
- very severe reaction before VIT
(syncope, hypotension, severe respiratory distress)
- systemic reaction during VIT
- honeybee allergy
- increased basal serum tryptase levels.

CONDITIONS FOR HIGH RISK OF RELAPSE AFTER
DISCONTINUATION OFVIT

STOP VENOM IMMUNOTHERAPY CRITERIA
 Individual basis
 Duration 3-5 years (5 years better than 3 years; longer treatment recommended in high-risk patients;
3 years may be sufficient in children)
 Undetectable sIgE or Negative skin test
• Expert: Suggest repeat test q 3-5 years but not required
• Persistent positive test: 80-90% no SR when resting after 3-5 years
 Relapse rate
• High risk pt.(previous table)
• duration 5 years < 3 years
• Adults > children
 Continue carrying epinephrine autoinjector based on risk factors

ASSESSING EFFECTIVENESS
 sIgG
 sIgE
 Skin test
 Sting challenge
sIgG
- Reflect exposure
- Not correlate with the presence of absence of an allergic sting reaction
- Specific IgG, IgE/IgG ratio not correlate to response to VIT
- Not recommended
sIgE
-Used in research but is not routinely used in clinical practice to
monitor the progress or success of VIT.

ASSESSING EFFECTIVENESS
 sIgG
 sIgE
 Skin test
 Sting challenge
Skin test
- Tend to become smaller and will revert to negative
- Most experts repeat skin testing when deciding whether or not to stop VIT after
five years of treatment, although this practice is not based on controlled trials
Sting challenge
- used in research but are not recommended for routine clinical practice
- Lack of response on a single sting challenge does not guarantee that the
patient will not react to a subsequent sting

PREGNANCY
 Same as other AIT
• Avoid beginning/build up
• Can be continued maintenance IT
 Discuss risk & benefit to pt.(individually)
• Risk of SR during VIT and risk of anaphylaxis esp. in sting season

PATIENT EDUCATION:CARRY EPINEPHRINEAUTOINJECTOR

Hymenoptera venom hypersensitivity 2020

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Hymenoptera venom hypersensitivity 2020

Similar to Hymenoptera venom hypersensitivity 2020 (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Hymenoptera venom hypersensitivity 2020