Hymenoptera venom hypersensitivity 1 (focused on apidae & vespidae)

Hymenoptera Venom Hypersensitivity
(Focused on Apidae & Vespidae)
Thitima Kantachatvanich, M.D.

Case female 41 years
• History of insect sting reaction 2 times
• Chest pain, N/V, no diarrhea, no rash, no syncope
• Winged insect
• Skin test and sIgE to hymenoptera negative all
Consult for evaluation
• What should you do next?

Classification
• Kingdom Animalia (Animals)
• Phylum Arthropoda (Arthropods)
• Subphylum Hexapoda (Hexapods)
• Class Insecta (Insects)
• Order Hymenoptera (Bees, Wasps, Ants)
• Greek hymen 'membrane' + pteron 'wing'.
Arthur Helbling, Ulrich R. Müller: Allergic Reactions to Stinging and Biting Insects, Clinical Immunology 5th edition

Taxonomy

มดไอ้ชื่นดำ =
http://www.ped.si.mahidol.ac.th/HA/pdf/leaflet/Allergy/ภาวะการแพ้อย่างรุนแรงต่อแมลงมีพิษในประเทศไทย.pdf

Taxonomy
Provespa

Family: Apidae
• Honeybee (Apis mellifera)
• Bumblebees (e.g., Bombus terrestris)
• Lose sting when stinging  sting one times and die exc. Bumble bee
• Most stings occur in summer and fall
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 118 (2017) 28e54
Pediatric Allergy & Primary Immunodeficiency Diseases 1st edition 2012

Honeybee (Apis mellifera)
• Spring, summer, warm winter days
• Nest: natural hollows
• Lose their barbed sting when stinging
• Rarely sting, only defensive
African-European Hybrid Bee/Africanized Bee/Killer Bee (Apis mellifera scutellata)
• Similar appearance of honeybee
• Unusual tendency to swarm & sting in large numbers
• Very limited cross reactivity with honeybee

Bumblebees (e.g., Bombus terrestris)
• Larger and more hairy > honeybees
• Most: yellow or white bands on abdomen
• Able to sting several times (not die after stinging)

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***

Vespula
• Waxy smooth body, 2 pairs of wings
• Wasps in Europe /yellow jackets in the US
• Most aggressive genus
• Sting for no apparent reason, particularly in the autumn
• Nest: ground, in attics, or in shelters
• Ingest sweet/grilled/leftover food, fruit in garbage
• Some yellow jacket spp. leave the sting

Dolichovespula (the New World Hornets)
• E.g. yellow hornet, white-face(bald-face) hornet
• Nest: tree branches or under the roofs
• Sensitivity to vibration  defensive sting behavior

Vespa (the True/Old World Hornets)
• the 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

Provespa
• Attracted to bright lights
• Ingest small insects
• Less aggressive, only defense

Polistinea: Paper Wasp
• Variable coloring
• Narrow waist and dangling legs when in flight
• Less aggressive than yellow jackets and hornets
• Nest: single layer of open cells (i.e., comb)
• Minimal outer covering
• On the eaves or windowsills of a home and on the railings of wood

Polistes fasculatus: Ceriana wasp ,
Wasp-mimic Hoverfly (หมาร่า/แมงหยอด/แมงไย๋)
• Not aggressive
• Isolated behavior
• Nest: hollowed ground

Family: Formicinae (Ant)
Import fire ant
• True sting apparatus: mandible and sting at abdomen
• Multiple stings: sting in half circle area
• Nest: ground, house, buildings
• Not painful
• The 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***

Hymenoptera Venom Allergy: Current Clinical Medicine 2nd edition 2010

Venoms: Toxin  Non-immunologic Reaction
• Vasoactive substances
• Histamine, dopamine, norepinephrine
• Acetylcholine
• Kinins
• Enzymes  phospholipase, hyaluronidase, apamim(neurotoxin)
• Systemic toxic effect (within 24hr to 6 days)
• Dose dependent (multiple stings)
• Rhabdomyolysis, intravascular hemolysis, ATN, myocardial injury,
hepatic injury, brain edema, coagulopathy

Venoms: Allergens  Immunologic Reaction
• Major allergen: >50% patient have allergic to
• 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)

Allergen: Apis mellifera
D.Antolín-Amérigo, et al.: Component-resolved diagnosis in
hymenoptera allergy, Allergology and Immunopathology, 2018

Allergen: Other Apis spp.
Allergen Name
Apis cerana Api c 1 Phospholipase A2
Api c 2 Hyaluronidase
Api c 4 Melittin
Apis dorsata Api d 1 Phospholipase A2
Api d 4 Melittin
Apis florae Api fl 4 Melittin
Similar PLA2 of various bee  significant cross reactivity among Apis spp.
Pediatric Allergy & Primary Immunodeficiency Diseases 1st edition 2012D.Antolín-Amérigo, et al.: Component-resolved diagnosis in

Allergen: Bombus pennsylvanicus
Allergen Name
Bom p 1 Phospholipase A2
Bom p 2 Hyaluronidase
Bom p 3 Acid phosphatase
Bom p 4 Serine protease
Unique PLA2 of various bumble bee  limited cross reactivity among bombus spp.
53% PLA2 of apis is identical to bombus  variable cross reactivity between apis & bombus spp.
Pediatric Allergy & Primary Immunodeficiency Diseases 1st edition 2012D.Antolín-Amérigo, et al.: Component-resolved diagnosis in

Allergen: Vespidae
Phospholipase of vespid ≠ bee
Extensive cross-reactivity among vespidae

Allergen: Formicidae
• Venom :95%toxin(alkaloid) and 1%allergen
Significant cross-reactivity among the various fire ant (Solenopsis species)
Not cross with other hymenoptera
D.
Antolín-Amérigo
et
al.

Clinical Presentations
• Large reaction(LR)
• Large local reaction(LLR): >10 cm
• Generalized cutaneous reaction
• Systemic anaphylactic reaction
• Systemic toxic reaction
• Unusual reaction

(Normal) Local Reaction
• Toxic effect
• Resolve in few hours (<24hr)
• Solenopsis: pustule heals after 1-2 week

Large local reaction(LLR)
• Larger than 10 cm, can crossing joint line
• Develop within minute to hours
• Lasting over 24 hr, subside after 3-10 days
• May cause lymphangitis/lymphadenopathy, non specific systemic
symptom(fever, malaise)
• Complication: Compartment syndrome, AW compromise
• IgE(80% of patient) or cell mediated mechanism or both
• Restinging  <5% anaphylaxis

Systemic Allergic Reaction
• Generalized cutaneous reaction
• Systemic anaphylactic reaction
• Usually IgE mediated > IgG, complement(IgG-venom complex)
• Severity α age
onset after stinging, number of sting
head&neck region(high vascular supply)

Unusual Reaction
• Rare
• After hours to days (> 4 hours)
• Serum sickness like
• Peripheral neuropathy, polyradiculomyelitis, EPS, ADEM
• AGN, AIN
• Vasculitis
• Hemolytic anemia, thrombocytopenia, HSP

Risk Factor for Severe Reactions to Stings
90% Adults with systemic reaction  severe
70% Children with systemic reaction  mild
Time interval between stings < 2 months
Less number of stings per year
abnormal metabolism of mast cell mediators
sIgE to bee > 1.0 kU/L  12X SR
BBs  ↑only SSR not all SR
Bee: high vol of venom  SR 50%
(vespid  SR 25-39%)
> 5 ng/ml -> ↑severe anaphylaxis

Natural History
Middlieton 8th edition

Natural History
Clinical Immunology. Principle and Practice 5th edition

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)

History
• 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

Clinical examination
• Vital sign
• Oxygen saturation
• Skin lesion
• Presence of sting
• EKG 12 lead (if clinical suggest)

Investigation
• Serum tryptase
When to do?
Strong recommendation
Upper limit: 11.4 ng/ml by Phadia AB. ImmunoCAP
Abnormal test  ↑Severe reaction before/during/post VIT

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

What to do?
• Recognize increased risk of reaction and VIT failure or relapse
• Monitor
• Consider BM biopsy: look for indolent mastocytosis
• VIT indefinitely & continue to carry 2 epinephrine auto-injectors

Skin test & sIgE
• Indication:
1. VIT candidate (anaphylaxis or LLR with frequent unavoidable
exposure or +IgE)…even past Hx is so long times ago or interrupted by
w/o reaction event
• Identify culprit insect
• Choose reagent for VIT
2. Mastocytosis (even w/o Hx of reaction)
*>20% of adults w/o Hx of reaction  IgE positive………..(Poor PPV)

Skin Test: Initial Test
• SPT: up to 100 mcg/ml  not considered by allergists
• IDT: start at 0.001-0.1 mcg/ml
 ↑10X q 20 min if negative until 1 mcg/ml
*Adverse effect of skin test: rare systemic reaction
*1-step method: only 1.0 mcg/ml (Not increase frequency of SR )

Skin Test Recommendations
• North America, Europe
• 0.02-0.03 ml
• Positive: wheal 3-5 mm greater than negative control with appropriate flare at
conc. </= 1 mcg/ml
• UK
• 0.03 ml
• Positive: wheal 3 mm greater than negative control at 20 min
• ALK’s package
• 0.05 ml
• Positive: wheal 5-10 mm with flare 11-20 mm

In Vitro Test: Venom-specific IgE
• Complementary to skin test or alternative test
• Negative skin test or unable to do(dermatographism, severe skin disease)
• 20% pt. with positive skin test  undetectable sIgE
• 10% pt with negative skin test  positive sIgE (high sensitive)
• Test all 5 venoms except for definitely known culprit
• Positive: > 0.35 kU/L
• Clinical significance of 0.1-0.35 kU/L???  consider in low total IgE

Basophil Activation Test
• Usually conc: 0.1-1 mcg/ml
• Improve sensitivity and specificity from serum sIgE
• Not routinely use
• For Dx and monitor VIT effectiveness

Component Resolved Diagnosis
• 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%

Component Resolved Diagnosis
• 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 diagnosis in hymenoptera allergy, Allergy Immunopathol 2018

Skin Test and In Vitro Test
• 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)
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 118 (2017) 28-54

When to Perform Venom sIgE(both skin & In
Vitro Test)?
• 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

Challenge Stings
• Some suggest for selection of VIT candidate
• NPV ≠ 100%
• 20% negative sting challenge  react after second challenge
• Require special center: risky
• Impractical as a general prerequisite for VIT

Family history
• Not correlated with sting reaction
• Not recommend to do any test

Treatment (Long term)
• Epinephrine autoinjector
• For Hx of anaphylaxis, LLR+other RFs(CVS, ↑sting risk) or pt.prefer
• Medical identification bracelet
• Refer for allergist (in case of allergic reaction)
• Consider VIT
• Preventive management

VIT Efficacy
• Untreat: 60% subsequent SR
• VIT: 5% subsequent SR
• Honeybee efficacy: <85%
• Vespid efficacy: >95%
• Also effective in delayed anaphylaxis
• Lessen severity than pre-VIT

VIT Indication
• Anaphylaxis + sIgE(in vitro) or skin test
• LLR + frequent unavoidable exposure
• Cutaneous systemic reactions + RFs(CVD, BBs, ACEI, tryptase, QoL,
frequent exposure)
• New recommendation: both children, adults  not require VIT
(Old: Children </= 16 years  not require VIT)
***No study comparing VIT & unTx
Sting challenge study: very unlikely to have severe anaphylaxis

Already Receiving VIT Adults:
Stop or Complete?
• Discuss risk & benefit individually
• Risk of VIT > Benefit from VIT  Stop
• E.g. SR during VIT
• Benefit from VIT > Risk of VIT  Complete

BSACI(the British Society for Allergy and Clinical
Immunology) 2011: VIT Recommendations
• Anaphylaxis or adult with cutaneous systemic reaction + sIgE or skin
test positive
• Duration = 3 years
Indefinitely
• During VIT  Still has reaction
• After VIT  Continuing risk of multiple stings
• Elevated baseline tryptase or mastocytosis

EAACI 2017
• Adults and children with moderate-to-severe allergic reactions
• Adult with systemic sting reactions confined to generalized skin
symptoms if QoL is impaired
• Lifelong VIT can be 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 during VIT
• H1 antihistamine: ↓LLR and mild systemic reaction (not anaphylaxis)
• Epinephrine autoinjector during and after VIT: only in patients at risk
of multiple stings or with risk factors for relapse

Procedure of VIT
• 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 react or
true dual sensitivity
• CRD to differentiate cross reactivity of allergen or
carbohydrate portion

Dosage Schedules
• Initial dose: up to 1 mcg (0.01-1)
• Buildup dose schedule
• Conventional: to maintenance in 2-4 months
• Modified rush: to maintenance in 2 months
• Rush: to maintenance in 2-3 days
• Ultrarush: to maintenance in in 4-8 hr  SR 0-28%
• Maintenance: at least 100 mcg of each venom (50 mcg for child)
• Honeybee sting = 50 mcg/sting
Same risk of SR (5-10%)

VIT duration
12-18 months
• q 1 month
then
• q 6-8 weeks
>4 years
• q 3 months
• Maintenance
• US FDA: indefinitely q 1 month
12-18 months
• q 1 month
12-18 months
• q 1.5 month
then
• q 2 monthExpert regimen
Commonly used

Examples of VIT Schedule
Package insert for Hollister Stier venom extracts(Spokane,Washington). ALK-Abello venom extracts (Round Rock, Texas).

SR During VIT:
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)

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
• Reduce dose 20-50% or start with caution
*SR to VIT is not significant affected by BBs, ACEI (conflicting evidence)
*Carry epinephrine autoinjector in high risk of SR

Adverse effects
• 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
• 5 years
• Extended or indefinitely in high risk

Stop VIT Criteria
• Individual basis
• Duration 3-5 years
• 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)
• 5 years < 3 years
• Adults > children
• Continue carrying epinephrine autoinjector based on risk factors

Further Need
• Markers of susceptibility
• Markers of tolerance

Pregnancy
• Same as other AIT
• Avoid beginning/buildup
• 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 Epinephrine
Autoinjector
Wear long shirt, pants, gloves when working outdoor
Keep insecticides approved for stinging insects

To be continued partII (Formicidae)

Hymenoptera venom hypersensitivity 1 (focused on apidae & vespidae)

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