Insect Venom Allergy: Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist, Cleveland Clinic
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

There are over 50 reported deaths per year due to insect stings in the U.S. The most common stinging insects are bees and wasps. They can cause severe allergic reactions including anaphylaxis and anaphylactic shock. Reactions to wasp stings are more common than those to bees.


Figure 1. Mind map of insect venom allergy (click to enlarge the image).

Classification

Bee and wasp venoms are different. Both contain hyaluronidase but differ in the content of other allergens. Patients allergic to wasp are rarely allergic to bee.

Sensitization

People are rarely stung by wasps -- once every 10-15 years. Sensitization to wasp venom can occur after a single sting. In contrast, allergy to bee venom occurs after frequent stings by bees. Consequently, most people allergic to bees are beekeepers or neighbors of beekeepers.

IgE antibodies to Hymenoptera venom are present in 20-30% of adults who had an insect sting in the previous 2-3 years.

Reaction to Wasp	Reaction to Bee
More common	Rarer
After a single sting	After many stings
Typical narrow waist and little hair	Hairy "fuzzy" bee

Table 1. Comparison of allergic reactions to wasp and bee venom.


Figure 2. A yellow jacket wasp with a typical narrow waist (left) and a honey bee with a fat hairy "fuzzy" body (right). Image source: Wikipedia 1, 2, GNU Free Documentation License.

Different Stinging Insects - How to Distinguish Them?

Yellow jacket, Vespula spp.

Yellow jackets are picnic and trash can scavengers. They are very aggressive, especially

in summer and autumn when larger populations compete for food supplies. They often sting for no apparent reason. Yellow jackets are responsible for most human stings.

Yellow jackets build their nests in the ground and are encountered during yard work,
farming, and gardening. When you see flying hymenoptera around garbage can or foods, think yellow jacket.

Hornets, Dolichovespula arenaria and maculata (yellow hornet and white faced hornets)

Hornets are extremely aggressive and build large nests in trees or shrubs. Nests are often found around human dwellings. Sensitivity to vibrations (e.g. lawn mower) sets off their defensive sting behavior.

Wasp, subfamily Polistinae (paper wasp)

Wasps build honeycomb nests in shrubs and under eaves of houses or barns. Nests are often found on window sills of homes. Wasps have a narrow “wasp waist” and dangling legs when in flight. They are less aggressive but can sting repeatedly without losing sting apparatus.

Wasps, yellow jackets and hornets, are scavengers, often at outdoor events where food and drink are being served. When you see flying hymenoptera around garbage can or foods, think yellow jacket.

Honeybees

Domestic honeybees are found in commercial hives. Wild honeybees build their nests in tree hollows or old logs.

Honeybees only sting once -- when they sting, their stinger comes out and they die. Wasps can sting multiple times, they can be aggressive and chase their victims.

Bumblebees are an important cause of sting reactions in some settings. Bumblebee
venom allergy is distinct from honeybee venom allergy and requires specific
testing.

Fire ant, Solenopsis invicta

Fire ants (red or black) are very aggressive and build large nests in mounds of fresh soil which are subterranean. Fire ants widespread in the southeast U.S. They have a true sting apparatus and can deliver multiple stings. Characteristic sterile pustule develop at the site within 24 hours after the sting.

Clinical features

Normal reaction: pain, erythema, a small area of edema (less than to 1 cm diameter).

Allergic reactions can be:
- local
- generalized

Local reactions

Edema can affect a hand/foot or even an entire limb, it can lead to blistering. Symptoms begin within 15 to 30 minutes and arise distant from the site of sting. Not dangerous unless it affects the airway.

How do you define a large local reaction to insect sting?

- increase in size for 24 to 48 hours,
- swelling to more than 10 cm in diameter
- 5 to 10 days to resolve

Patients who have experienced large local reactions often have large local
reactions to subsequent stings, and up to 10% might eventually have a systemic reaction.

What is the difference between a large local reaction and a systemic cutaneous reaction?

Systemic reactions can include a spectrum of manifestations ranging from mild to life-threatening:

- cutaneous reactions (eg, urticaria and angioedema),
- bronchospasm
- large airway obstruction (tongue or throat swelling, laryngeal edema)
- hypotension and shock.

The key feature that distinguishes a systemic cutaneous reaction from a large local reaction is the involvement of parts of the body not contiguous with the site of the sting.

Large local reactions are usually late-phase IgE-mediated, with large severe swelling (8-10 inches in diameter) developing over 24 to 48 hours and resolving in 2-7 days.

Generalized (systemic) reactions

Systemic allergic reactions occur in 1% of children and 3% of adults. Children generally have a more benign course after insect stings because they usually have only cutaneous systemic reactions. Remember:

C
Children
Cutaneous only

A
Adults
Airway
Anaphylaxis

Systemic reactions often start with erythema and pruritus, followed by urticaria and facial or generalized angiooedema.

Patients often feel extremely ill, as if they are going to die ("a sense of impending doom"). SOB can occur due to laryngeal edema or bronchospasm. In severe reactions, hypotension leads to lightheadedness and loss of consciousness. Less common features: abdominal pain, incontinence, chest pain, blurry vision.

The onset of generalized reactions is usually within 10 minutes of a sting.

It is important to check serum tryptase in all patients undergoing workup for venom allergy to rule out indolent mastocytosis.

Only 70% of patients with stinging insect allergy fill their epinephrine prescriptions (Rudders, Annals 2013).

Diagnosis

- History
- Venom-specific IgE antibodies (ImmunoCAP)

Many patients say the sting was from a bee when it is was from an wasp. Vast majority of patients (except beekeepers) will be wasp allergic.

History should be confirmed by demonstrating specific IgE against wasp or bee venom. This is done first by skin test (prick or intradermal) and/or second by blood test (ImmunoCAP).

Skin tests are positive in 65-80% of patients with a history of systemic allergic reactions to insect stings. ImmunoCAP (specific IgE) is less sensitive than venom skin tests and can lead to false positives.

Remember:

Allergy = clinical reactivity
Sensitization = specific IgE antibodies, can occur without clinical reactivity (allergy)

Patients are rarely allergic to both bee and wasp venom.

Extracts

Allergen (venom) vaccine is the recommended term for the therapeutic agent used in allergen immunotherapy. "Vaccine" is used when the therapeutic use of the preparation is
clear. "Extract" is used when the non-therapeutic aspects of the allergen preparation are discussed.

Extracts of honeybee, yellow jacket, white-faced hornet, yellow hornet, and wasp venom are available for skin testing and VIT.

There is no venom extract for fire ant hypersensitivity but a hole-body extract is available.

Tests

Although the negative predictive value of testing in venom allergy is very high, the positive predictive value is much lower.

Baseline serum tryptase is an important predictor of the severity of sting reactions, the frequency of systemic reactions during VIT, the chance of VIT failure, and the risk of relapse if VIT is stopped.

Skin prick tests with a concentration in the range of 1.0 to 100 mcg/mL may be performed before intracutaneous (intradermal) tests but are not used by all allergists.

Intradermal (intracutaneous) tests start with a concentration in the range of 0.001 to 0.01 mcg/mL. If intracutaneous test results at this concentration are negative, the concentration is increased by 10-fold increments until a positive skin test response occurs or a maximum concentration of 1.0 mcg/ mL is reached.

A positive intradermal skin test to insect venom at a concentration of 1.0 mcg/mL or lower is indicative of specific IgE antibodies. False positive results to intradermal testing can occur at venom concentrations greater than 1 mcg/ml, therefore such doses are not recommended for diagnosis.

Skin testing with fire ant whole-body extract is indicative of specific IgE antibodies if a positive response occurs at a concentration of 1:100 wt/vol or less by prick method, or 1:1000 wt/vol or less by intradermal method.

If the skin test is negative despite a convincing history of anaphylaxis after
an insect sting, in vitro testing for IgE antibodies or repeat skin testing is recommended.

Refractory period of “anergy”

Negative skin testing in the days or weeks after a sting reaction may be

due to a refractory period of “anergy”. For these patients, the skin test should be

repeated after 4-6 weeks.

There is no "ideal" test. ImmunoCAP does not correlate perfectly with skin test results, but both tests are useful they supplement each other. Serological testing is negative in up to 20% of skin-positive patients, and skin test are negative in up to 10% of patients found to have venom-specific IgE (positive ImmunoCAP).

Patients with a "good" history of venom allergy but negative skin tests should be evaluated with serologic testing. If serological testing is negative, the skin test should be repeated.

Acute management

Drugs: EASI

Epinephrine IM
Antihistamines PO, IM
Steroids PO, IM, IV
Inhaled b2-agonists, if wheezing

Treatment of choice is epinephrine with a 1:1,000 (1 mg per mL) aqueous solution. Adult dose is 0.3 mL, children dose is 0.01 mg per kg (maximum: 0.3 mL, i.e. one adult dose). Dose can be repeated every 10-15 minutes, up to 2-3 times but in practice repeat administration is generally avoided since high doses of epinephrine can induce arrhythmias.

Patients taking beta blockers can be relatively resistant to epinephrine effect.

Further management

- Desensitization (immunotherapy)
- Self medication with EpiPen

Desensitization (immunotherapy)

Immunotherapy causes a switch from the abnormal Th2 cytokine response to a Th1 response.

Venom immunotherapy has a 98% efficacy but carries a 10% risk systemic allergic reaction and can cause anaphylaxis.

Initial course of weekly injections over 3 months (12 weeks), reaching the highest dose of 100 mcg (equivalent to two stings). Then, maintenance injections of 100 mcg monthly for 5 years. Patients are observed for 30-60 minutes after each injection.

The maintenance dose is 100 mcg for each venom to which the patient has a positive skin test. Mixed vespid venoms (total dose of 300 mcg) are most commonly used.

It is easier to remember that patients come to the office once a week for 12 weeks for their injections. At the end of the 12 weeks, they have been desensitized to the bee stings. Then, they come once a month, for a minimum of five years. Some high-risk patients should be treated indefinitely.

The incidence of systemic reactions with insect venom immunotherapy (10-15%) is similar to inhalant allergen immunotherapy. Less than 50% of reactions require epinephrine injection.

Up to 50% of patients experience large local reactions. Such local reactions are not associated with an increased risk of systemic reactions to subsequent injections.

Venom immunotherapy (VIT)

30-60% of patients with a history of anaphylaxis from an insect sting who have venom-specific IgE antibodies (skin or in vitro testing) will experience a systemic reaction when stung again.

VIT is not necessary in children 16 years of age and younger who have experienced isolated
cutaneous systemic reactions without other systemic manifestations. They only have a 10% chance of having a systemic reaction if stung again, and if one occurs, it is unlikely to be worse
than the initial isolated cutaneous reaction.

VIT in adults who have experienced only cutaneous systemic reaction is controversial but usually recommended.

VIT is extremely effective in reducing the risk of systemic reaction to less than 5%, and sting reactions that occur during VIT are usually milder.

VIT is generally not necessary for patients who have had only a large local reaction because the risk of a systemic reaction is low.

The vast majority of patients who have had a large local reaction do not need to be tested for specific IgE.

What is the dose of VIT?

VIT injections start weekly, beginning with doses no greater than 0.1 to 1.0 mcg, and increasing to a maintenance dose of 100 mcg of each venom (e.g., 1 mL of a vaccine containing 100 mcg/mL of venom).

The dosage schedule for fire ant immunotherapy is less well defined. A maintenance dose
is 0.5 mL of a 1:100 wt/vol concentration.

The interval between maintenance dose injections can be increased to 4-week intervals during the first year of VIT and to every 6 to 8 weeks during subsequent years.

How long to continue VIT?

VIT should be continued for at least 3 to 5 years. Despite the persistence of a positive skin test response, 80-90% of patients will not have a systemic reaction to an insect sting if VIT is stopped after 3 to 5 years.

Some patients with a history of severe anaphylaxis with shock or loss of consciousness still might be at continued risk for a systemic reaction if VIT is stopped, even after
5 years of immunotherapy.

Patients who have experienced a systemic reaction carry injectable epinephrine (eg, EpiPenTM or TwinJectTM devices) at all times.

Patients who take beta-blocker are at greater risk for anaphylaxis to VIT or a sting. Patients who have stinging insect hypersensitivity should not be prescribed beta-blockers unless absolutely necessary.

Self medication

- Oral antihistamines to take as soon as patient is stung
- Syringes preloaded with epinephrine (EpiPen TM)

Epinephrine auto-injector comes in 2 forms: EpiPen, 0.3 mg and EpiPen Jr., 0.15 mg.

EpiPen delivers epinephrine within seconds to minutes and "buys" the victim 20 minutes to get to the nearest emergency room. Some patients will have delayed reactions to the insect venom and this is the reason why they still have to go to the ER to be observed for 3-6 hours.

EpiPens expire every 18 months and it is recommended to have 2 of them handy.

Patient Recommendations

Patients who have a history of a systemic reaction to an insect sting should:

- avoid stinging insects
- carry epinephrine for emergency self-administration
- undergo testing for specific IgE antibodies to stinging insects
- be considered for venom immunotherapy (VIT) if test results for specific IgE antibodies are positive
- carry medical identification of stinging insect hypersensitivity

References

Stinging Insect Hypersensitivity: A Practice parameter Update. Joint Council of Allergy, Asthma, and Immunology.
Clinical review: ABC of allergies, Venom allergy. Pamela W Ewan. BMJ 1998;316:1365-1368.
Stinging Insect Allergy. David B. K. Golden. American Family Physician, June 15, 2003.
Patient information. Tips to Remember: Stinging insect allergy. AAAAI.org.
Anaphylaxis to stings and bites. Robert J Heddle. MJA 2006; 185 (5): 290.

Stinging Insect Guidelines - 2001 Update by AAAAI and ACAAI. Medscape, 2011.

Related reading

'Tongue Drops' Cut Bee Sting Allergy. WebMD, 03/2008.
Fire Ant Stings. Consultant, Vol. 46, No. 13, November 2006.
CNN: Skateboarder's death underscores insect allergy risks. 5 percent of Americans are at risk for a severe, potentially life-threatening allergic reaction from insect stings http://bit.ly/3PEVtK

Beebearding is thought to date back to the 1700s http://goo.gl/j4nE
Bee Aware Allergy - Insect allergy educational website by Hollister-Stier Laboratories.
Hymenoptera-Sting Hypersensitivity - NEJM review, 2014 http://buff.ly/1mEZX8z

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