Stinging Insects

Hymenoptera
Apidae
Vespidae
Formicidae
  • Honeybees
  • Bumblebees---
  • Yellow jackets
  • Aerial nesting yellow-jackets
    • Yellow hornets
    • Bald (White) faced hornets---
  • Paper Wasps
  • Fire ants
Venom allergens
  • Honeybees
    • Api m 1 - Phospholipase A2
    • Api m 2 - Hyaluronidase
    • Api m 3 - Acid Phosphatase
    • Api m 4 - Melittin
    • Api m 5 - Dipeptidylpeptidase IV
    • Api m 6 - Cystein-rich trypsin inhibitor
    • Api m 7 - CUB serine protease
    • Api m 8 - Carboxylesterase
    • Api m 9 - Serine carboxylesterase
    • Api m 10 - Icarapin
    • Api m 11 - Major royal jelly protein
    • Api m 12 - Vitellogenin
  • Bumblebees
    • Phospholipase, hyaluronidase, acid phosphatase (as above)
    • Protease (tryptic amidase specificity)
    • Fraction 4
  • Dol m 1 - Phospholipase A1
  • Dol m 2 - Hyaluronidase
  • Dol m 3 - Acid phosphatase
  • Dol m 5 - Antigen 5
  • Venom contains 99% alkaloids and 0.1% proteins, including:
    • Sol i 1 - Phospholipase (cross-reactive with wasp phospholipase)
    • Sol i 2 - protein unique to S. invicta
    • Sol i 3 - Antigen 5-like protein (but not cross-reactive with wasp antigen 5)
    • Sol i 4 - protein unique to S. invicta

Note: Api m 10 appears to be a significant allergen which is labile and may not survive venom extract processing for IT, which may account for the lower efficacy of honey bee venom IT

Hymenoptera_table.png

Note:
  • The 2 species of imported fire ant in the USA are Solenopsis invicta (red, dominant species) and Solenopsis richteri (aka black imported fire ant, minor species), both capable of eliciting IgE-mediated reactions
  • Disturbance of a fire ant mound results in a swarm of thousands of ants that respond by stinging anything the ants contact



Allergen Cross-reactivity

Major cross-reactivity between:
Limited cross-reactivity between:
"None"
  • Bee species
  • Yellowjacket species (except V. squamosa)
  • Wasp species
  • Yellow jackets and yellow hornets, bald-faced hornets
  • Yellow hornets and bald/white faced hornets
  • Wasps and other vespidae (yellowjackets, yellow hornets, bald/white faced hornets)
  • Fire ant and other venoms
  • Bees and other species
  • When cross-reactivity observed between honeybee and vespidae, it is thought to be due to cross-reacting carbohydrate determinants (see below for management of "double positive" specific IgE testing)
  • Api m 2 (hyaluronidase) shares substantial sequence identity with hyaluronidase of other flying Hymenoptera and may play a role in "double positive" testing
Venom_cross-reactivity.png

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Clinical symptoms


Definitions

Small local (normal/expected) reaction
  • Redness, swelling, itching, pain, may last for several days, occurs in most people who are stung
    • Intense local inflammation may cause the appearance of lymphangitic streaks in the first 24-48 h (not to be mistaken for cellulitis)
  • Fire ant sting results in sterile white 1-2 mm pseudopustule within 24 hours
Large local reaction
  • Swelling to more than 5-8 cm in diameter
    • Defined by BSACI as an "area of induration with a diameter of >10 cm and which peaks between 24 and 48 h and then subsides"
  • Possible involvement of more than one joint area
  • Potentially life-threatening if stung somewhere in the airway
  • Increase in size for 1-2 days after sting, peak at 2-3 days, resolves 5-10 days
Cutaneous systemic reaction
  • Includes generalized urticaria, flushing, pruritus, angioedema at site(s) other than local reaction
  • Note that systemic reactions in children that are limited to the skin are not considered to be anaphylactic reactions
Anaphylaxis
  • May include cutaneous reactions with bronchospasm, airway obstruction, hypotension, shock
  • The slower the time of onset of signs and the symptoms of anaphylaxis, the less likely the reaction will progress to a life-threatening event
  • In some patients, there is sudden hypotension (collapse and loss of consciousness) with no other features
  • In fatal cases, average time from sting to death is 10-15 min
Toxic/Unusual reactions (not IgE-mediated)
  • Commonly after multiple simultaneous stings (e.g. attack by Africanized honeybee swarm)
    • Toxic reactions from multiple stings (usually >50): Renal failure, rhabdomyolysis, cerebral oedema, haemolysis, clotting disorders, sting site necrosis
  • Serum sickness, vasculitis
  • CNS: Neuropathies, Guillain-Barre syndrome, myasthenia gravis, acute encephalopathy; seizures (fire ant)
  • Delayed cold urticaria in IgE positive individuals
  • Hematologic: TTP, Henoch–Schonlein Purpura, hemolysis, coagulation defects
  • Renal: acute renal failure due to interstitial nephritis/tubular damage, nephrotic syndrome
  • Alveolar Hemorrhage
  • Direct sting to eye causing corneal damage and cataract
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Diagnosis


Diagnostic Criteria

  1. Sting resulting in a system reaction
  2. Positive intradermal skin test and/or specific IgE to hymenoptera
    • Test only if indicated (see below)


Identify Insect

  • Identification assists diagnosis and guides recommendations for avoidance
Factors in history for insect identification
Activity-----------------
Hedge clipping or lawn mowing might disturb yellow jacket or hornet nests
Location
Sting occuring near the eaves of a house where Polistes wasps nest or near an open garbage can that attracts yellow jackets
Time of year
  • Yellow jackets are more prevalent in late summer
  • Wasps and hornets in the spring and early summer
Food
  • Food attracts yellow jackets, patients have been stung in the mouth, oropharynx, or esophagus while drinking a beverage from a container that contained a yellow jacket
  • Hornets and wasps also feed on human food and cause stings around food or trash
Part of country
  • Wasps are more prevalent in Texas and Louisiana
  • Fire ants are more prevalent in states located along the Gulf Coast and in the southeastern states
  • Africanized honeybees reported in Texas, New Mexico, Arizona, Nevada, and California
Stinger left in skin
Usually associated with a honeybee but occasionally also with other insects (bumblebees, yellow jackets)
White pustule
Fire ant stings typically present as lower extremity papules that develop into white sterile pustules over 24 hours
IFA quarantine area.jpg

Indications for Testing

  • In general, test only patients who are candidates for venom immunotherapy (VIT)
  • Note that the mere presence of venom sIgE is associated with at least a 5-10% chance of systemic reaction
Patient Type
Testing/VIT Indicated?
Note
Any patient without history of a sting reaction (even with positive family history of venom allergy)
No
  • Up to 27% of general adult population has detectable venom-sIgE (30-40% in the weeks after a sting)
  • Screening of general healthy population in fire ant-endemic areas have shown elevated fire ant sIgE in 38.3% of children (35.7% in children 2-5 yo, 57.5% in 11-20 yo) and 17% in adults
  • In a study of patients with negative history and incidental positive SPT or sIgE (including components), sting challenge caused LLR in 43.6% (9.5X unsensitized general population) and systemic reaction in 5.3% (similar to general population)
  • Positive family history does not increase risk
Patient with frequent large local reactions that are debilitating/progressively worsening and who cannot avoid stinging insects (due to work, etc)
Yes
  • Usually caused by an IgE mediated late-phase response and carry <5-10% chance of future systemic reaction (<2% severe)
  • VIT can successfully prevent future large local reactions
>16 years old with systemic reaction/anaphylaxis to sting (even if event occured decades ago and even if reaction limited to skin)
Yes
  • VIT indicated, especially with severe systemic reaction history; risk of another systemic reaction ranges up to 70-75% (30% severe) and can persist for many years (10-20) after index reaction
  • VIT for isolated cutaneous reactions generally not recommended in Europe/UK
  • Arguing against VIT for >16 year old with mild/moderate index systemic reactions are prospective sting challenge studies which showed only 1% incidence of more severe reactions than previous; in general, adults with cutaneous index reaction have 10-20% chance of future systemic reaction (<5% severe)
Adult patient with moderate-severe anaphylaxis to sting taking beta-blocker that cannot be discontinued
Yes
  • VIT indicated because the risk of anaphylaxis related to a venom sting is greater than the risk of VIT systemic reaction
  • A strategy to consider is to hold beta-blocker during up-dosing and restart it after the patient has reached maintenance
Adult patient with systemic reaction/anaphylaxis to sting taking ACE-inhibitor that cannot be discontinued
Yes
  • ACE inhibitors have been associated with greater risk for more severe reaction from VIT and field stings.
  • VIT indicated in cases where no alternative for the ACEI exists and VIT is judged to be favorable from risk/benefit standpoint and consideration of patients’ preferences.
  • No evidence exists that ARBs increase risk
Adult patient with systemic reaction/anaphylaxis to sting taking both beta-blocker and ACE-inhibitor that cannot be discontinued
Yes
  • Concomitant administration of both of these medications in a patient who requires VIT might be warranted, if favorable, from an individualized assessment of potential risks and benefits and patients’ preferences.
≤16 years old with systemic reactions limited to skin (urticaria, angioedema, flushing, pruritus)
No (hymenoptera except fire ant)

Maybe (fire ant)
  • 10% chance of future systemic reactions
  • <3% chance that a future reaction will be more severe than the index reaction, <1% chance that a future reaction will be life-threatening
  • Because the natural history of fire ant allergy in children with only cutaneous symptoms has not been well elucidated and avoidance is difficult, fire ant IT might be considered
  • Limited evidence suggests that children who initially have LLRs or cutaneous systemic reaction do not progress to more severe reactions with future stings
≤16 years old with anaphylaxis due to sting
Yes
  • VIT indicated
  • 32% of children who have moderate–severe systemic reactions have reactions of similar severity following re-stings, even 10-20 years after index reaction
Patient with toxic/unusual reaction (serum sickness, etc.) due to sting
Maybe (serum sickness)

No (other toxic reactions)
Recurrence of serum sickness has not been observed after initiation of VIT and VIT has been used successfully in this group of patients, but the safety and efficacy of this approach is unknown
  • Apart from above, factors affecting decision to do VIT include elevated baseline tryptase, very rapid onset of reactions, advanced age, absence of cutaneous signs, likelihood of future stings (bee keeping or occupational exposure), remoteness from medical help, effect on QOL, patient preference and co-morbid conditions
Euro indications for VIT.png
Management of sting reactions.png


Skin Testing


Protocol
  • Allow 4-6 weeks to pass after sting episode to decrease chance of false negative skin test (results can be negative in 20-50% during the 4-6 week refractory period)
  • If stinging insect cannot be identified, test with venoms from all relevant insects found in the area where sting occurred
    • In the US, this typically includes honey bee, yellowjacket, yellow hornet, white-faced hornet, and wasp (and/or fire ant depending on history/geographic area)
    • If able to positively identify fire ant as the stinging insect, testing with other venoms is not indicated
  • Procedure for all venoms except fire ant:
    • Consider initial screening SPT with 100 mcg/mL if patient with history of severe anaphylaxis who may be highly sensitive
      • Golden: I never do SPT for venom
    • Start intradermal (ID) skin testing at 0.001-0.01 mcg/mL
      • Test then proceeds at 20-30 minute intervals with 10-fold increases in concentration until a positive skin test occurs or a max concentration of 1 mcg/mL is reached
      • Golden: for vespids (including wasp), may proceed to 3 mcg/mL step
  • Procedure for fire ant:
    • Initial screening SPT with whole body extract
    • If SPT negative, start ID skin testing with whole body extract at 1:1,000,000 weight/volume
      • Test then proceeds at 20-30 minute intervals with 10-fold increases in concentration until a positive skin test occurs or a max concentration of 1:1000 or 1:500 is reached
Allergen
SPT Step 0 - for history of severe anaphylaxis with apidae/vespidae
(mcg/mL)
Wheal/Flare---
(mm)
ID Step 1 (mcg/mL)
W/F
(mm)---
ID Step 2 (mcg/mL)
W/F
(mm)---
ID Step 3 (mcg/mL)
W/F
(mm)---
ID Step 4 (mcg/mL)
W/F
(mm)---
ID Step 5 (per Golden)
(mcg/mL)
W/F
(mm)-
Honey bee venom
100

0.001

0.01

0.1

1

N/A

Yellowjacket venom
100

0.001

0.01

0.1

1

3

Yellow hornet venom
100

0.001

0.01

0.1

1

3

White-faced hornet venom
100

0.001

0.01

0.1

1

3

Wasp venom
100

0.001

0.01

0.1

1

3

Fire ant (whole body extract)
1:100 (weight/vol)

1:1,000,000

1:100,000

1:10,000

1:1000 or 1:500

N/A

Histamine
1 mg/mL

0.1 mg/mL


Negative control
Extract diluent

Extract diluent




Interpretation
  • Golden:
    • For SPT: wheal at least 3 mm greater than negative control is positive
    • For ID skin testing:
      • Reactions of 1+ or greater (i.e. ≥5 mm wheal + ≥11 mm flare, with wheal at least 3 mm larger than the negative control) at a concentration of 1 µg/mL or less of venom indicate the patient is venom sensitive
      • Honeybee venom is inherently irritating therefore 1+ criteria (≥5 mm wheal/≥11 mm flare) may be appropriate for vespids and 2+(≥5 mm wheal/≥21 mm flare) may be appropriate for honey bee
        Golden pos ven st.png
      • For vespids/wasps, if skin test reaction is equivocal at 1 mcg/mL, perform test at 3 mcg/mL (based on many years experience with this technique showing either no greater reaction or a clearly positive response)
    • Skin test reaction size or concentration at which reaction occurs does not predict severity of future reactions
      • The strongest skin test reactions often occur in patients with only LLRs (very low risk of anaphylaxis), whereas some patients with abrupt and near-fatal anaphylaxis show only weak skin test (or serologic) sensitivity; ~25% of patients with systemic sting reactions are positive only at the 1 µg/mL concentration
  • If skin testing is negative in a patient with a suggestive history:
    • Obtain serum specific IgE
    • Consider repeat skin testing in 6-12 weeks if sIgE negative


Specific IgE Testing

  • Indicated if skin test is entirely negative or if unable to perform skin test.
    • Also consider obtaining if a specific insect is strongly suspected (e.g. stinger left behind), yet the skin testing was negative for that insect
  • Level ≥0.35 kU/L considered positive
  • Phadia ImmunoCap sIgE tests available:
    • Bumble bee
    • Yellowjacket
    • European hornet
    • European paper wasp/Mediterranean paper wasp
    • Paper wasp/Common paper wasp
    • White-faced hornet
    • Yellow hornet
    • Fire ant
    • Venom allergen components
      • rApi m 1
      • rVes v 1
      • rVes v 5
      • rPol d 5
    • ISAC microarray
      • nApi m 1
      • nApi m 4
  • Johns Hopkins venom sIgE high sensitivity assay

Double positive sIgE
  • With skin testing, positive results are more likely to be seen only to the venom to which the individual is truly sensitized.
  • Positive to both bee and yellow jacket
    • 30% with venom allergy are positive to both bee and yellow jacket allergens on sIgE testing, but individuals clinically allergic to both types of venoms is rare. This may be due to 50% sequence identity of hyaluronidases and cross-reactive carbohydrate determinants between venoms and plants (e.g. pollens).
    • If doubt remains, sIgE to recombinant rApi m1 and rVes v5 often identifies the causative insect
  • RAST inhibition testing (available from Johns Hopkins) may also discern between species-specific and cross-reactive IgE (e.g. discern if elevated wasp sIgE is due to specific wasp IgE or cross-reactive yellow jacket sIgE, and vice versa)


Note
  • Combination of skin testing and sIgE testing (with the high-sensitivity Johns Hopkins assay if necessary) detects 98% of patients who will have a systemic reaction to a future sting.
  • sIgE level does not predict severity of future reactions




Tryptase Level

  • An elevated baseline tryptase level occurs in 5-10% of patients with anaphylaxis to stings and in up to 25% with hypotensive reactions
  • BSACI: baseline tryptase should be checked in all patients with systemic reactions to venom
  • Measurement of baseline serum tryptase level is especially recommended in patients with moderate or severe anaphylactic reactions to stings
    • Severe anaphylaxis (with hypotension) due to insect sting may be presenting sign of occult systemic mastocytosis or a mast cell activation syndrome
    • Obtain baseline serum tryptase level after the patient has returned to their baseline state. Further evaluation (laboratory studies and bone marrow biopsy) is indicated in patients with baseline serum tryptase >20 ng/mL, and should be considered for levels >11.4 ng/mL if the patients has signs or symptoms suggestive of a mast cell disorder.
      • Several patients have been reported with tryptase levels as low as 5 ng/ml that reacted to hymenoptera sting despite negative skin/sIgE tests to venom and were found to have underlying systemic mastocytosis
    • Increased tryptase levels are associated with more frequent/severe anaphylactic reactions to stings, more system rections during VIT, greater failure rates with VIT, and greater relapse rates after stopping VIT
  • Tryptase is not always positive during acute anaphylaxis with sting


Other Tests

  • Total IgE - it has been observed that a level >250kU/L is more likely to indicate asymptomatic sensitization and such patients may be protected from severe anaphylactic shock and loss of consciousness
  • Basophil activiation test (BAT) - patient's basophils are incubated with venom allergens, following which basophil activation is measured by detecting CD63/203c with flow cytometry. Correlates well with skin testing and sIgE but is not available commercially.


Systemic Reaction with Negative Tests

  • 2% with negative skin/blood testing despite all the above recommended testing
  • Repeat skin testing in 3-6 months
  • Carry epinephrine during evaluation
  • Anecdotal reports of these patients being successfully treated with VIT if the venom is based on the results of a sting challenge.
  • Several patients have been reported with tryptase levels as low as 5 ng/ml that reacted to hymenoptera sting despite negative skin/sIgE tests to venom and were found to have underlying systemic mastocytosis


Sting Challenge

  • Done at major research centers
  • Results of sting challenge may not always predict results of a field challenge
  • 20% of patients who do not react to a sting challenge will react after a second challenge, limiting its predictive value



Treatment

  • Routine treatment of systemic reactions and anaphylaxis
  • If a barbed stinger is present, removing the stinger by flicking or scraping (not pulling) the stinger away with a fingernail or credit card within the first 10-20 (maybe 30) seconds might prevent injection of additional venom
  • Discuss avoidance and provide handout
    • No evidence currently exists that wearing perfume or bright, floral-colored clothing elevates sting risk
  • Small local reactions
    • Ice, cold compress
    • Oral antihistamines
  • Large local reactions
    • Above + oral steroids (3-5 days)
    • VIT may reduce size/duration of these reactions.
      • Consider VIT if reactions are frequent and disabling, particularly if there is unavoidable occupational exposure
    • Carry epinephrine (in case future reactions are more severe) - usually NOT necessary but might be considered if it provides reassurance to the patient
  • History of systemic reaction to sting with positive testing
    • Venom immunotherapy if indicated (see indications for testing table above)
    • Carry epinephrine, H1 antihistamine
      • Casale: in children, a cutaneous reaction with diffuse urticaria is not indicative of anaphylaxis and typically does not require the use of epinephrine; in adults, epinephrine should be considered for urticaria alone
    • Allergy identification card and/or bracelet
  • History of systemic reaction to sting with negative testing
    • Negative skin tests/sIgE are not a guarantee of safety, and patients with suspected higher risk should be counseled about avoidance, use of epinephrine, and emergency care of allergic reactions.



Venom Immunotherapy



Natural Course

  • Risk of systemic reaction in untreated patients with history of sting reaction and positive venom skin tests:

Risk of systemic
reaction (%)

Original sting reaction
Age
1–9 years
10–20 years
Note
No reaction
Adult---
17

  • Tests became negative in 30–50% of these individuals after 2–5 years
  • Up to 27% of general adult population has detectable venom-sIgE
Large local
All
10
10

Cutaneous systemic---------------------
Child <17 years old---
10
5
  • <3% chance that a future reaction will be more severe than the index reaction

Adult
20
10

Anaphylaxis
Child <17 years old
40
30


Adult
60
40

Middleton 7th Ed.

Golden venom SR natural hx.png


Note
  • Spontaneous improvement is common, a substantial proportion of patients (20–100% in different studies) with a history of a systemic reaction to a sting have no such reaction to a subsequent sting
  • Patients with severe initial reactions have the highest risk of a recurrence.
  • Recurrent systemic reactions to venom tend to be similar in severity to the initial reaction in an individual patient.
  • The chance of a patient experiencing a more severe reaction to a future sting by the same insect is small, and declines only slightly over time.


References