Insect allergy

L A L I TA T E A R P R A S E RT

Insect allergy4 Nov 2016

• Epidemiology

• Etiology

• Taxonomy

• Insect venom

• Clinical features

• Evaluation & Diagnosis

• Treatment and Prevention

• Predictors of risk for sting anaphylaxis

• Venom immunotherapy

Outline

• 56%-94% of adults worldwide have been stung a least once in their lifetime

• Can occur any age

• Only a weak correlation with other allergic conditions

• Most reactions are localized and self limited

- Large local reaction 5-25%

- Systemic reactions

>> Children 0.4-0.8%

>> Adults 3%

Epidemiology

Middleton's Ed 8. Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137.

• Stinging insects belong to the order Hymenoptera

• Sting apparatus is a modified ovipositor, only the female

insects can sting

• Almost sting primarily in defense of themselves and their nest

Etiology


TaxonomyHymenoptera

Formicidae (Ant)

Vespidae (Vespid)

Apidae (Bee)

PolistinaeVespinae

Vespula (Yellow Jacket)

Vespa (Hornet)

Dolichovespula (White-Faced &Yellow Jacket)

Polistes (Paper Wasp)

Apinae

Bombus (Bumblebee)

Apis (Honeybee)

Myrmecinae

Provespa (ต่อนอนวัน)

Family

Order

BombinaeSubfamily

Genus

Ponerinae

Pachycondyla (มดปุยฝ้ายจั่วจีน)

Pseudo Myrmecinae

Odontoponera (มดไอ้ชื่นดำ)

Diacamma (มดหนามคู่สีเทา)

Tetraponera (มดตะนอย)

Solenopsis (Fire Ant)

Adapted From : Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137.

วิภาดา ปาริยะประเสริฐ และนวลอนงค์ วิศิษฏสุนทร . โรคภูมิแพ้จากแมลงต่อย. ศิริราช 353-94.

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Family Apidae

• Feral honeybees often nest in natural hollows such as in trees

• Domestic honeybees : Rarely sting or swarm without considerable

provocation, mostly in defense of their nest and their queen

• "Sting autotomy"

Sting apparatus of the honeybee is barbed and breaks away

from the insect body when it remains in the skin after a sting

and leads to its deathMiddleton's Ed 8.

Apis (Honeybee)(ผึ้งน้ำหวาน)

• Unusual tendency to swarm

with little provocation and to

sting in large numbers

• Large numbers of stings at one time can cause toxic reactions --> Fatal to human • Not found in Thailand

Middleton's Ed 8. National Pest Management Association

Bombus (Bumblebee)(ผึ้งหึ่ง)

• Not aggressive and do not usually sting

• Very uncommon causes of sting

• “fuzzy” appearing hair and loud buzzing sound

• Report to cause anaphylaxis during occupational exposure

especially in areas of higher exposure (e.g., greenhouse

workers)

• Found in Northern of Thailand

• Very limited cross-reactivity with honeybee sting reactions



• Apis mellifera : Western honeybee

(ผึ้งพันธ์ุต่างประเทศ)

• Apis florea : Dwarf honeybee

(ผึ้งมิ้ม)

• Apis cerana : Asiatic honeybee

(ผึ้งโพรง)

• Apis dorsata : Giant honeybee

(ผึ้งหลวง)

Apis (Honeybee)(ผึ้งน้ำหวาน)

Thailand

Bombus (Bumblebee)(ผึ้งหึ่ง)

Middleton's Ed 8. วิภาดา ปาริยะประเสริฐ และนวลอนงค์ วิศิษฏสุนทร . โรคภูมิแพ้จากแมลงต่อย. ศิริราช 353-94.

Family Vespidae

Middleton's Ed 8. Makoto Matsuura. The Social Biology Of Wasps.


Provespa (ต่อนอนวัน)• Typical nocturnal habits (peak:1-3 hr. after sunset)

• Nest in shrubs or trees

Thai : Provespa Barthelemyi Provespa Anomala

• Use a wood pulp to construct nests that contain one or more

layers of comb, each of which contain a large number of cells, attached in a vertical arrangement and usually are enclosed in

papier mâché outer layers

• Does not commonly autotomize, and vespids are able to

sting repeatedly

Vespa (Tropical Hornet)(ต่อหัวเสือ)


Thai : Vespa Affinis Vespa Tropica

Polistes (Paper Wasp)(ต่อกระดาษ)

• Narrow wasp waist and dangling legs when in flight

• Commonly build nests on human habitation

• Nest limited to single-layer of open cells with minimal outer covering

• Generally not aggressive but can sting readily when disturbed and can sting repeatedly

• Very commonly mistaken for a yellow jacket, as it is black, strongly marked with yellow

Thai : Polistes SagithariusMiddleton's Ed 8.


Vespula (Yellow Jacket)• Scavengers

• Seek their food at picnics and in orchards, trashcans, and dumpsters

• Highly aggressive and sting for no apparent reason

• Nests are located in the ground or in cracks in buildings or

residential landscape materials

• Not found in Thailand


Dolichovespula (White-Faced & Yellow Hornet)

• Their sensitivity to vibration can initiate their defensive sting behavior

• Not found in Thailand


Family Formicidae• When they bite, they anchor by their mandibles and

pivot to administer multiple stings • Unique lesions : "sterile pustules" within 24 hr. that can

become infected if excoriated or opened


Solenopsis (Imported Fire Ant)(มดคันไฟ)


Pachycondyla (มดปุยฝ้ายจั่วจีน)Odontoponera (มดไอ้ชื่นดำ)

In Thailand

• Solenopsis germinata

• Solenopsis invicta (Red imported fire ant)

• Solenopsis richtera (Black imported fire ant)


Middleton's Ed 8. Bilò Mb, Et Al. Allergy 2005; 60: 1339-49.

• Typically contain a mixture of 3 to 4 major proteins

• Contain active peptides, vasoactive substances and enzymes

• Common proteins shared amongst the various Hymenoptera species

• Major allergens primarily protein enzymes : phospholipase,

hyaluronidase, and acid phosphatase

- Glycoproteins of 10-50 kDa containing 100 – 400 amino acid residues

Insect venom

• Toxin

• Vasoactive amines (histamine,

dopamine, norepinephrine)

• Acetylcholine

• Kinins


burning, pain, itching

renal failure, rhabdomyolysis

• Honeybee : PLA2 (Api m1)

• Vespid : Antigen5 (Ves v 5)

Allergenic component(Major allergen)

Non-allergenic component

Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137. Ollert M. Curr Allergy Asthma Rep (2015) 15: 26.

ApidaeApi m1

Api m2

Api m3

Api m7

Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137.

VespidaeVes v1

Ves v2

Ves v5

Phospholipases found in vespid venoms (PLA 1)

differ from those found in bee venoms (PLA 2)

Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137.

Formicidae

Sol i1

Sol i3

• 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

Venom Dose


Between family

• Less common between honeybee and the other venoms

• Limited cross-reactivity exists between the antigens in

fire ant venom and the antigens in venoms of other

Hymenoptera

• Different insect families have almost no cross-reactivity

Middleton's Ed 8. David B.K. Golden, Et Al. Stinging Insect Hypersensitivity. Practice Parameter 2016.

Cross-reactivity

• Bumblebee show very limited cross-reactivity

with honeybee sting reactionsApidae family

Vespidae family• Extensive cross-reactivity in different genus

esp. hornet (vespa) and yellow jacket (vespula)


Within family

Formicidae family • limited cross-reactivity

David B.K. Golden, Et Al. Stinging Insect Hypersensitivity. Practice Parameter 2016.

Hymenoptera

Formicidae (Ant)

Vespidae (Vespid)

Apidae (Bee)

PolistinaeVespinae

Vespula (Yellow Jacket)

Vespa (Hornet)

Dolichovespula (White-Faced &Yellow Jacket)

Polistes (Paper Wasp)

Apinae

Bombus (Bumblebee)

Apis (Honeybee)

Myrmecinae

Provespa (ต่อนอนวัน)

Family

Order

BombinaeSubfamily

Genus

Ponerinae

Pachycondyla (มดปุยฝ้ายจั่วจีน)

Pseudo Myrmecinae

Odontoponera (มดไอ้ชื่นดำ)

Diacamma (มดหนามคู่สีเทา)


Solenopsis (Fire Ant)

Adapted From : Pesek Et Al. Allergy Asthma Immunol Res. 2013 May; 5(3):129-137.


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Cross-reactivity

• Classified as “local” or “systemic” in distribution and

an “immediate” or “delayed” time course

• Most insect stings are transient local reactions

- pain, swelling, and redness usually last from

a few hours to a few days and generally resolve


Clinical features

• Limited to the area contiguous with the sting site

• Redness, Swelling, Itching and pain

• Late-phase, IgE-dependent reaction

• Increase in size for 24 to 48 hours

• Larger than 10 cm in diameter, and can

involve an entire extremity (crossing joint lines)

• Not dangerous except for potential local anatomic

compression, especially on the head, neck, tongue, or throatMiddleton's Ed 8.


Local reaction

Large local reaction (LLR)

Systemic reaction (SR)• Typically IgE mediated

• May present with a variety of symptoms, involving multiple organ

symptoms

1.) Cutaneous systemic reactions are limited to skin manifestations

2.) Anaphylaxis includes hypotension or involvement of at

least 2 organ systems

3.) Systemic toxic reaction

- Non-IgE mediated (anaphylatoid reaction) : onset < 24 hr.-6 days

- ex. Renal failure, rhabdomyolysis, DIC, N/V, diarrheaMiddleton's Ed 8.


Middleton's Ed 8. Thomas B. Casale, Et Al. N Engl J Med 2014;370:1432-9.


• Unusual reactions of unknown mechanisms are usually delayed (> 4 hr.) :

sickness-like reactions, encephalitis, peripheral and cranial neuropathies,

glomerulonephritis, myocarditis, and Guillain-Barré syndrome.

Kounis syndrome (Allergic angina)

most

Brehler R, Et Al. Curr Opin Allergy Clin Immunol 2013, 13:360–364. Matysiak J, Et Al. Ann Agric Environ Med. 2013; 20(4):875–879.

Grading of systemic reactions

Grading Muller Ring & Messmer

I Generalized urticaria, periorbital edema, itching, malaise, anxiety

Cutaneous manifestations (flushing, pruritus, urticaria, angioedema)

IIAngioedema or

two or more of following: chest/throat tightness, nausea,vomiting

Mild respiratory, CV, GI (Rhinorrhea, hoarseness, dyspnea,

tachycardia, BP change, arrhythmia)

IIIDyspnea, wheezing, or stridor or

two or more of following: dysphagia, dysarthria, hoarseness, weakness,

confusion, feeling of impending diaster

Severe multisystem involvement (Laryngeal edema, bronchospasm,

anaphylaxis, cyanosis, shock, collapse)

IV Hypotension, collapse, loss of consciousness, incontinence, cyanosis Cardiac arrest

Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.

Evaluation & Diagnosis

• Diagnosis requires a clear, thorough medical history

• Quite high sensitization rate (positive tests to hymenoptera venom

but with a negative history)

• However, people with a clear documented history of a venom

reaction can have negative tests, and occasionally testing can be

positive to both honey bee and wasp venom

• Diagnosis of insect sting allergy rests on the history as the primary

evidence

- Nature and timing of stings in the past

- Time course of the reaction

- All associated symptoms and treatments

- Number of stings and the location on the body (systemic or local reactions)

- Concurrent medications : β-adrenergic blocking agents, ACEIs

(contribute significantly to the severity of the anaphylactic reaction)

- Underlying disease : heart disease

- Medications used for treatment of the reaction

Clinical history

Middleton's Ed 8.

Identity of the culprit insect :

- notoriously unreliable part of the history

- location and timing of the sting or the location of the nest

may suggest the type of insect

Middleton's Ed 8.

• In Vivo

- Skin prick test (SPT)

- Intradermal test (ID)

- Sting challenge

• In Vitro

- sIgE : RAST

- Serum tryptase

- Basophil activation test (BAT)Middleton's Ed 8.

Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86. D.B.K. Golden / Ann Allergy Asthma Immunol 111 (2013) 84-89.

Diagnostic tests

Purpose

1.) Confirm allergic sensitization

2.) Define the risk of future systemic

reaction to stings (Candidates VIT)

Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86. David B.K. Golden, Et Al. Stinging Insect Hypersensitivity. Practice Parameter 2016.

• Should be performed at least 2 weeks after a sting reaction,

ideally 1–2 months later in case of false negatives due to a refractory

period after a sting

• Sensitivity : SPT < ID

• Increasing doses in 10-fold increments of venom traditionally have

been used for either SPT or ID

SPT & ID (Apid, Vespid)

SPT : Start 1.0 µg/mL (max 100 µg/mL)

ID : Start 0.001-0.01 µg/mL (max 1 µg/mL)

If >1.0 mcg/ml : nonallergenic ingredients can cause nonspecific reaction (False positive)

WWW.drugs.com

Venom extract

• Honey Bee (Apis mellifera)

• Yellow Jacket (Vespula spp.)

• Yellow Hornet (Dolichovespula arenaria)

• White Faced Hornet (Dolichovespula maculata)

• Wasp (Polistes spp.)

• Mixed Vespid (Yellow Jacket, Yellow Hornet & White Faced Hornet)

http://www.drugs.com

Tracy Et Al. Curr Opin Allergy Clin Immunol 2015, 15:358–363.

• Difficulty in collecting all species for the yellow-jacket and paper wasp

venom mixes, not all lots contain every species

Thailand

(Freeze-dried venom)

WWW.drugs.com

Shelf life

12 mo.

1 mo.

2 wk.daily

http://www.drugs.com

Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86. Rutcharin Potiwat. Asian Pac J Allergy Immunol 2015;33:267-75.

David B.K. Golden, Et Al. Stinging Insect Hypersensitivity. Practice Parameter 2016

SPT & ID (Fire Ant)

• Imported fire ant whole-body extract

• Screening SPT : 1:1000 (w/v) of imported fire ant WBE

• Intradermal skin test :

- initial concentrations of approximately 1 x 10-6 (1:1 million) wt/vol.

- increased by increments until a positive response is elicited or a

maximum concentration of 1 x 10-3 (1:1,000) or 2 x 10-3 (1:500) wt/vol

Interpretation

Thomas B. Casale, Et Al. N Engl J Med 2014;370:1432-9.

Positive skin test

• ID skin test

- Inconsistency in the description of the technique and interpretation

- No definitive studies to suggest any specific intradermal technique

to be superior for determining specific IgE for venom


North America, Europe, and many

countriesUnited Kingdom ALK

(manufacture)

MethodInjection of 0.02 - 0.03 mL of venom to produce a bleb

of 3 mm

Injection of 0.03 mL of venom to raise a bleb of 3 to 5 mm.

Injection of 0.05 mL of venom

Interpretation

- wheal 3 - 5 mm. > negative control

- with appropriate surrounding erythema

- wheal 3 mm. > negative control

- at 20 minutes

- wheal 5 - 10 mm and erythema 11 - 20 mm

Negative skin test

• Patients with a convincing history but negative skin test results

may consider

- Refractory period of anergy : skin tests should be repeated

after 4 to 6 weeks

- Confounding medicine

- Not used culprit insect

- Maybe non-IgE mediated


" If skin test results are negative in a patient with a clear history of systemic sting reaction, further testing (in vitro testing, repeat skin testing , or both) should be performed, as well as basal serum tryptase "

Middleton's Ed 8. Golden. Immunol Allergy Clin North Am. 2007 May ; 27(2): 261–Vii.

• Skin test results for individual venoms can vary over a short period,

and identification of all sensitivities requiring treatment may require

skin testing on 2 separate occasions

• The strongest skin tests often occur in patients who have had

only large local reactions and have a very low risk of anaphylaxis

" If negative skin test results and a convincing history of anaphylaxis should be further investigated with serologic testing, and if results

remain negative, the skin tests should be repeated after 3 - 6 months "

• Sensitivity of venom sIgE is generally lower than ID

• sIgE increased in days-week maximum 2-3 week after sting than

gradually decrased

• Perform for "Whole body extract" or "Components" (Natural or

Recombinant components)

- Natural venom extracts can lead to clouding of the diagnostic

process secondary to cross-reacting carbohydrate determinants

(CCDs) ex. HBV, YJV

sIgE

Middleton's Ed 8. Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.

D.B.K. Golden / Ann Allergy Asthma Immunol 111 (2013) 84-89.

Ollert M, Et Al. Curr Allergy Asthma Rep (2015) 15: 26.

Cross-reactivity carbohydratedeterminants (CCD)

• In insects, the relevant CCD epitope is defined by an alpha-1,3-linked fucose residue at the innermost N-acetylglucosamine of the carbohydrate core structure

Ollert M, Et Al. Curr Allergy Asthma Rep (2015) 15: 26. Brehler R, Et Al. Curr Opin Allergy Clin Immunol 2013, 13:360–364.

• IgE antibodies with specificity for the alpha-1,3-fucose epitope are responsible for approximately 75 % of double sensitizations to HBV and YJV

• Clinical relevance of these IgE antibodies appears to be rather low

Insect

MMF3F6: represents a typical structure

Plant

Brehler R, Et Al. Curr Opin Allergy Clin Immunol 2013, 13:360–364. Matysiak J, Et Al. Ann Agric Environ Med. 2013; 20(4):875–879.

• IgE antibodies reacting with bee and wasp venom (Double sensitivity)

could be detected in about 30–50% may be due to 3 causes

(1) independent sensitization to both venoms (rare)

(2) cross-reactive IgE antibodies against to common protein

Hyaluronidase (Api m2 & Vas v2) or dipeptidylpeptidase

(Api m5 & Vas v3)

(3) cross-reactive IgE antibodies against CCD

Double sensitive to bee & wasp

Darío Antolín-Amérigo, Et Al. Curr Allergy Asthma Rep (2014) 14:449. Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.


• Api m 1 (major honeybee allergen) : low sensitivity

• Ves v 1 & Ves v 5

- Ves v 5 : good diagnostic performance

- Ves v 5 & Ves v 1 : sensitivity was significantly increased

• Pol d 1 & Pol d 5

• Crucial especially when the stinging insect was not identified

and when skin tests and specific IgE to the native allergens are

unsuccessful for the identification

Recombinent marker allergen

MUXF3 : glycan from bromelain is commercially available

Darío Antolín-Amérigo, Et Al. Curr Allergy Asthma Rep (2014) 14:449.

Example

Decreased false-positive and false-negative

Ollert M, Et Al. Curr Allergy Asthma Rep (2015) 15: 26.

• Cannot performed skin test

• Disconcordant between history and skin test

- sIgE test is positive in 10% of patients with negative skin test results

• Double sensitization

- 50% of allergic reaction to honey bee or vespulae had positive both

diagnostic test (homology in the hyaluronidase enzymes) ,

CRD can help to identify true culprit insect

Middleton's Ed 8. Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.


sIgE benefit in patients

The level of sensitivity (skin test or serum IgE) is correlated

with the frequency but not the severity of the reaction

Golden. J Allergy Clin Immunol 2005;115:439-47.

• Venom skin tests and venom-specific IgE assays correlate imperfectly

sIgE negative in 20% of skin test–positive

skin test negative in 10% of persons with elevated IgE antibodies

Basophil activation test (BAT)

Before test : Basophil > 50 cells

Matysiak J, Et Al. Ann Agric Environ Med. 2013; 20(4):875–879. D.B.K. Golden / Ann Allergy Asthma Immunol 111 (2013) 84-89.


Can be useful in

• In cases of negative skin tests and negative specific IgE

results or discrepancies in these tests

• Monitoring of VIT results

" Routine use of BAT in evaluating Hymenoptera sensitive

patients is not recommended "

• Remains to be standardized in terms of methodology

and interpretation

• Should be done : severe anaphylaxis

• Evaluation : Mastocytosis or mast cells diseases

• Predict : Severity of systemic reaction to sting

Serum tryptase



Mast cell disorders

• Insect stings are the most common

cause of anaphylaxis in mastocytosis

• 25% of insect sting anaphylaxis --> have elevated baseline serum tryptase

• 2% mastocytosis --> insect sting anaphylaxis

Middleton's Ed 8. Rueff Et Al. J Allergy Clin Immunol 2009;124:1047-54.


• If the serum tryptase is elevated (>11.4 ng/ml) bone marrow biopsy should be considered

• Tryptase concentrations manifest a significant correlation with severity of clinical symptoms, especially with a decrease in blood pressure in the main arteries

Sting challenge

• Sting challenge is the most specific diagnostic test, but unethical and impractical

• Recommended by some to better select those patients who need VIT

Middleton's Ed 8. Agache Et Al. Allergy 70 (2015) 355–365.

Www.Eaaci.Org

Absolute contraindication

- Pregnancy

- Acute inflammatory disease

- Severe or uncontrolled cardiovascular or respiratory disease

- Treatment with beta-blockers

http://www.eaaci.org

• Low negative predictive value (NPV) : A single negative challenge sting does not preclude anaphylaxis to a subsequent sting

• Less reliable with vespids than with honeybeesMiddleton's Ed 8.

Agache Et Al. Allergy 70 (2015) 355–365. Www.Eaaci.Org

Limitation

• Same species as the one that provoked the reaction

• Sting has to be confirmed by the development of a wheal and flare reaction and by the characteristic burning pain

• After the sting challenge, all patients have to be observed for at least 2 hr in the hospital

http://www.eaaci.org


• Ice pack, elevation of the afftected limb

• Oral antihistamines • Large local reactions, especially head and neck

- Oral corticosteroid 40-60 mg of prednisone 5 days

(steroids should be started within few hours of sting in patients with known history of large local reactions) - Analgesic : NSAIDs • Antibiotics are not necessary

Treatment of acute reactionsLocal & Large local

Middleton's Ed 8.

• Urticaria may respond to antihistamines alone

• Anaphylactic reactions require epinephrine injection IM (1:1000)

0.01 mg/kg (max 0.3 mg in children, 0.5 mg. in adult)

• Patients who have history of rapid onset or very severe systemic

reactions may treatment immediately after the sting

• Hypotension should be supine with legs raised

• Delay in the use of epinephrine has contributed to fatal reactions

• Some individuals with anaphylactic shock are resistant to epinephrine

- Patients taking β-blocker medications Rx Glucagon Middleton's Ed 8.

Systemic reactions

• Anaphylaxis requires patient education before discharge

• Use of self-injectable epinephrine requires consistent instruction

and follow-up

• Referred for an allergy consultation : For VIT

• Preventive treatment : effective measures to avoid insect stings


Patient education

Pitfall

• Patients often fail to carry the injector with them

• Delay using when they have a reaction

Prevention

• Avoid eating outdoors

• Avoid flowering plants

• Avoid drinking from straws, cans, or bottles outdoors

• Remove fallen fruit or pet feces

• Cover trash cans

• Watch for nests in bushes or in the ground when mowing

• Avoid going barefoot outdoors

• Avoiding fragrances

• Avoiding brightly colored or floral clothing

• Using insect repellants

• Running; flailing the arm


Effective Ineffective

Predictors of risk for sting anaphylaxis

Natural history• Prognosis for affected patients is based on the understanding

of the natural history of the condition including clinical factors

and biologic markers

• Future sting will cause an allergic reaction depends on the history

and immunologic status of the patient

Middleton's Ed 8.

Middleton's Ed 8.


Clinical markers Laboratory markersVery severe previous reaction

Insect species

No urticaria/angioedema

Age (>45), Gender (male)

Medications (ACE inhibitors)

Multiple or sequential stings acetylhydrolase

Venom skin test

Venom-specific IgE

Basal serum tryptase

Platelet activating factor (PAF)

Angiotensin converting enzyme (ACE)

Predictors of risk of systemic reaction to insect sting


Venom immunotherapy• Treatment of choice for prevention of systemic allergic reactions

to insect stings but it requires careful selection of patients

• All patients who have experienced a systemic allergic reaction to

an insect sting and who have specific IgE to venom allergens

- reduces the risk of a subsequent systemic sting reaction to

as low as 5% compared with up to 60% in untreated patients

• High risk patients : patient with mastocytosis, or an increased basal

serum tryptase level


Indication for VIT

VIT

Middleton's Ed 8.

Change in practice parameter 2016

VITOptional

• VIT is generally not required for patients > 16 years of age who have

experienced only cutaneous systemic reactions

• Sting challenge studies suggest that these patients are very unlikely to have

severe anaphylactic reactions to subsequent stings

(Recommendation: C)


(1) Prevent systemic reactions

(2) Alleviate patients' anxiety related to insect stings

(with improved quality of life)


Goals of VIT

Only large local reactions to stings that VIT is generally not necessary

(low risk of a systemic reaction 4-10%) , but might be considered in

those who have frequent unavoidable exposure for quality of life reason

• Malignancy • Severe asthma

• Immunological conditions • Chronic heart and lung disease

• Severe hypertensions • Drug: beta blockers, tricyclic antidepressants, monoamine oxidase inhibitors, ACEIs • Initiation during pregnancy (though maintenance can be continued in pregnancy)

Contraindications


• 95-100% effective in preventing systemic reactions to stings

- maintenance dose of 300 μg of mixed vespid venoms

• 75-95% efficacy

- 100 μg dose of individual venoms

(i.e., honeybee, yellow jacket, or Polistes wasp)

• Fire ant IT using wholebody extracts has been reported to be

reasonably safe and effective

• Repeat sting reactions usually are milder than pretreatment reactions


Efficacy 95% to 100% effective in preventing

systemic reactions to stings

Failure of VIT

• Associated with - abnormal basophil activation test responses - underlying mastocytosis

Middleton's Ed 8.

Safety

Middleton's Ed 8. Darío Antolín-Amérigo, Et Al. Curr Allergy Asthma Rep (2014) 14:449.

• Adverse reactions to VIT are no more common than reactions

during inhalant allergen immunotherapy

• Systemic symptoms occur in 5-15% (Most are mild)

- Severe systemic reactions to injections --> underlying mast cell

disease

• LLR to venom injections ~ 50% of patients, esp. dose 20 - 50 μg

- LLR to venom injections not predicted systemic reactions

Risk factors for side effect during IT


• Antihistamines

- Reduce local and systemic reactions

• Leukotriene modifier

- Reduce LLR

• Recurrent systemic reactions to VIT: rush VIT, or omalizumab

Pre-medication


• Need only contain a single venom if the culprit is definitively

known

• Recombinant venom allergens has been able to resolve dual

sensitivity that may be due to CCD

• Mixed vespid efficacy > single vespid

• Therapy with yellow jacket or mixed vespid venoms can protect against

wasp stings

Venom species


• Increasing the maintenance dose up to 200 mcg per dose has

been effective in achieving protection in patients who had sting

reactions while receiving a 100-mcg maintenance dose of VITLudman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.


Venom Dose• Initial dose of up to 1 mcg

Increase to maintenance dose of at least 100 mcg of each venom

(equivalent to 2 honeybee stings : 50 mcg per sting)

• Children might be effectively treated with a maintenance dose of 50 mcg.Change in practice parameter 2016


Schedules Different in Build-up phase

1.) Build-up

1.) Traditional/ conventional : 4-6 mo.

2.) Modified rush/ cluster : 6-8 wk.

3.) Rush : 2-7 days

4.) Ultra-rush : < 2 days


4-6 mo.6-8 wk.2-7 days< 48 hr.

Middleton's Ed 8.

ConventionalModified

rush

• 2 standard regimens in the US. aim to achieve the 100-mg dose in either 8 or 15 weeks

• Rush VIT is indicated in some patients in Europe

Patella V, Et Al. Journal Of Allergy Volume 2012.

Ultrarush Rush

Unlike inhalant allergen IT, the more rapid regimens of VIT appear

to have the same or greater safety as the traditional regimen

2.) Maintenance

• Onset of protection with VIT is quite rapid

• Sting challenge studies : protective is reached after an 8-week

build-up regimen

Every 4 weeks for 12-18 months

Every 6 weeks for 12-18 months

then Every 8 weeks

Middleton's Ed 8. D.B.K. Golden / Ann Allergy Asthma Immunol 111 (2013) 84-89.

12-week interval may be effective for extended maintenance

treatment after 4 years of routine therapy

• Repeat skin tests or immunoassays : every 2-3 years

• SPT - After 5 years : negative < 20%

- After 7–10 years : negative 50–60%

(although most remain positive by RAST) • Venom-specific IgE antibody levels

- level rises during the first months of therapy - returns to baseline after 12 months

- declines steadily during maintenance treatment (even after therapy is stopped and after a sting)

Maintenance evaluation


• Venom-specific IgG antibodies

- marker of clinical efficacy

- good PPV but poor NPV

- confirm protective levels after initial therapy

(especially honeybee or single venoms)

- considered protective: ≥ 3 μg/mL during the first 4 years

Maintenance evaluation

Middleton's Ed 8 Ludman And Boyle. Journal Of Asthma And Allergy 2015:8 75–86.


Duration• Early studies : recommended 3 years (results included patients with

up to 10 years of treatment)

• Subsequent studies : 5 years of was associated with better

suppression of allergic sensitivity and lower risk of relapse


Change in practice parameter 2016• 5 years is better than 3 years

• Longer treatment recommended in high-risk patients; 3 years may be sufficient in children

Better for 5 years

25% 10%

2 yr.

> 5 yr.


Risk of relapse after discontinuing VIT

• No specific tests to distinguish which patients will relapse after stopping VIT

• Relapse

- 5 years < 3 years of VIT

- younger children < adults



Maybe need longer than 5 years

• Honeybee allergy

• Had systemic reactions to an injection or sting during VIT

• Elevated baseline serum tryptase levels

• Very severe sting reactions before treatment

• Mastocytosis

- recommend VIT for life

- efficacy of VIT is less than optimal in mastocytosis patients, they

should continue to carry 2 epinephrine injectors

• Patients who are not willing to accept the 10%- 20% chance of

reaction to a subsequent sting


Long-term extension of VIT


• The decision to stop immunotherapy can involve consideration

of several factors by the patient and physician

(1) severity of the initial reaction

(2) basal serum tryptase

(3) frequency of exposure

(4) presence of concomitant disease and medications

(5) effect of such action on work and leisure activities

(6) the patient's preferences

• Natural history of fire ant allergy is not as well described

• But clear need for effective IT

• IT using WBE : effective but no placebo-controlled trials

• The dosage maintenance schedule is less well defined

- most experts recommend maintenance dose : 0.5 mL ,1:100 wt/vol

- some experts : 0.5 mL , 1:10 wt/vol

• Duration is still uncertain, because discontinuation led to relapse

• Most allergists consider stopping after specified period (usually 3-5 years)

or only when skin test or in vitro test become negative


Fire Ant immunotherapy


50 mcg., 3 years

Thank You

Benefit in selected culprit For VIT

Health & Medicine

Insect allergy