Fire Ant Hypersensitivity: Understanding the Allergens

Fire Ant
Hypersensitivity
Onnicha Chaisetsumpan, MD
Division of Allergy, Immunology and Rheumatology
Unit, Department of Pediatrics
King Chulalongkorn Memorial Hospital

Outline
• Introduction
• Taxonomy
• Epidemiology
• Ant venom allergens
• Clinical manifestation
• Diagnosis
• Management

Introduction
• Ants are insects and belong to the order Hymenoptera and family Formicidae
• Ants are diversely spread among continents and biogeographic regions
• Currently more than 12,500 ant species known
• Tropical areas and continental forests: greatest influence on presence of ant species
diversity
• Some species of ants can bite and sting humans
• Only some ant genera (Solenopsis) cause life-threatening allergic reactions
• Ant hypersensitivity is one of the most important causes of severe systemic
reacttions or anaphylaxis with reports of fatalities occuring worldwide
Potiwat R, et al. Asian Pacific journal of allergy and immunology. 2015 Dec 1;33(4).

Taxonomy of Hymenoptera
Ant
Honeybee Bumble bee Yellow jacket Hornet Paper wasp
Jack
jumper ant
Fire ant Harvester ant
Ants are social insects classified in
family Formicidae, order Hymenoptera
Clinical Immunology: Principles and Practice 5th edition. 2019

Subfamily Scientific name Common name Thai name
Myrmicinae Solenopsis invicta Imported fire ant ไม่พบในประเทศไทย
Solenopsis richteri Imported fire ant ไม่พบในประเทศไทย
Solenopsis geminata Tropical fire ant มดคันไฟ
Ponerinae Tetraponera rufonigra มดตะนอยอกส้ม
Tetraponera pilosa มดตะนอยตาลแดง
Pachycondyla chinensis มดปุยฝ้ายจัbวจีน
Odontoponera denticulata มดไอ้ชืbนดํา
Diacamma rugosum มดหนามคู่สีเทา
Formicidae

Formicidae
• Worker ants vary size from 3 to 6 mm.
• Nests in mounds composed of freshly disturbed soil
• Very aggressive, particularly if their nests are disturbed
• Nest: ground, house, buildings
• Often responsible for multiple stings
• When they bites, they anchor by mandibles and pivot
to administer multiple stings
• Sterile pustules
Middleton’s allergy 9th edition. 2020

Imported fire ant (IFA)
•Solenopsis invicta
•Solenopsis richteri

Solenopsis geminata
• Differentiation of Solenopsis species
by morphology alone is difficult and
can often be confused with other
species
• Presence of two-segmented petiole
• Polymorphic size of 3-8 mm body
length
• Reddish brown color
• Mostly smooth and shinny without
sculpture
Formicidae
Solenopsis
(fire ant)
Myrmicinae
Pogonomyrmex
(harvester ant)
• S.invicta (red imported fire ant)
• S.richteri (black imported fire ant)
• S.geminata (tropical fire ant)
• S.xyloni (southern fire ant)
• S.aurea (desert fire ant)
• S.molesta (thief ant)
Family
Subfamily
Genus
Species

Solenopsis geminata
• S.geminata worker is
divided into two notches ≠
S.invicta absent notches
• Important stinging species
causing anaphylaxis in Asia

Solenopsis geminata
Nest structure
• Often found in an opened area, dry soil >
shadow area under trees
• They often make nest in safe place from flooding,
disturbing by human: under concrete of building,
under roots of trees or dead trees
• Usually occupy >1 meter in diameter and could
be >50 cm. depth depending on nature of soil
• Solenopsis geminata nests are flat compared to
Solenopsis invicta

Tetraponera rufonigra
• มดตะนอยอกส้ม
• Bi-colored appearance
• Dark head and gaster
• Variation in color of mesosoma and petiole
parts of body: usually light orange-brown in
color
• Two nodes on petiole segment
• Nests: small nests in cavity of dead or
dried parts of trees
Formicidae
Tetraponera
Pornerinae
rufonigra
Family
Subfamily
Genus
Species

Odontoponera denticulate
• มดไอ้ชืUนดํา
• Color: blackish brown
• Petiole: in lateral view, narrowly triangular
with straight anterior and posterior
margins
• Nests: wood habitats including forest
edges and disturbed area
Formicidae
Odontoponera
Pornerinae
denticulata
Family
Subfamily
Genus
Species

Tetraponera rufonigra and Odontoponera denticulate
Characteristics T.rufonigra O.denticulate
Body shape Two nodes on petiole
segment
• Single node
• Narrow node with a small
spine
Color Black and shinny except
orange-line on alitrunk
Formicidae
Tetraponera
Pornerinae
Odontoponera
rufonigra
Family
Subfamily
Genus
Species denticulata

Pachycondyla chinensis
• Asian needle ant, มดปุยฝ้ายจัUวจีน
• 3.4 to 5.0 mm in length
• Dark brownish-black color with orange-brown mandibles, legs,
antennae and stingers with yellowish hair
• Nests: forest floor in spring and fall, dead trees or below soil
surface in winter
Formicidae
Paychycondyla
Pornerinae
chinensis
Family
Subfamily
Genus
Species

Epidemiology • Imported fire ant = 2 non-native species:
Solenopsis richteri and Solenopsis invicta
• Solenopsis richteri
• Native to Uruguay
• Introduced into the U.S. in 1918 in the
ballast of cargo ships through port of
Mobile, Alabama
• Solenopsis invicta
• Native to Argentina
• Introduced into the U.S. in 1930s
• Dominant species of imported fire ant
Steigelman DA, et al. Annals of Allergy, Asthma & Immunology. 2013 Oct 1;111(4):242-5.

• In Thailand, 247 ant species distributed among
55 genera in 9 subfamiles have been reported
• Invasive ants: exotic species established colonies
outside native area, cause a decline or change in
diversity, community and populations of native by
their invasion
• Solenopsis geminata, Tetraponera rufonigra
and Odontoponera denticulata: most commonly
responsible for clinical hypersensitivity reaction in
Thai patients
• Imported fire ants (IFA) have not been detected
in Thailand
Epidemiology: Thailand
Srisong H, et al. Molecular Immunology. 2016 Jan 1;69:24-32.

Epidemiology: Thailand
• 32 children and adults with history of ant
anaphylaxis and positive results for specific
IgE or skin tests using S.invicta WBE
• Causative ant identification
• Species identification by taxonomist
• All patients were asked to bring the suspected
causative ants from areas they were stung
• Surveillance teams went to endemic areas to
collect ant samples by direct searching
37.5%
31.3%
6.25%
18.75%
Unable to provide sample of causative
ants but suspected S.geminata
Potiwat R, et al. APJAI 2018 Jun 1;36(2):101-8.

Ant venom
•Ant venom is usually injected from a
poison gland located at posterior part
of ant (gaster)
•Composed of various biologically active
peptides and protein components with
each ant species having variety of major
allergenic proteins
•Imported fire ant (S.invicta)= most
frequently studied ant venom

Ant venom
• Venom of imported fire ant is unique
• Low protein content and high concentration of alkaloid
• 90-95% water-insoluble piperidine alkaloid
• alkaline 2-methyl-6-n-alkyl and alkenyl piperidines
• Highly cytotoxic, bactericidal and hemolysis
• Cause a sterile pustule at the sting site: early wheal and flare, later pustule
formation
• 5% aqueous solution of proteins
• Seasonal variation in protein content of ant venom: higher in summer

Ant venom
2-5%
67%
20%
9%
% of total venom protein
• Soi i 1: 37-kDa protein with phospholipase A1 activity
• Soi i 2: 26-kDa protein, dissimilar to other sol allergen
• Soi i 3: 24-kDa protein, member of antigen 5 family
• Soi i 4: 13-kDa protein
Each S.invicta sting transfers
0.04-0.11 µL of venom
10-100 ng of proteins

Soi i 1 allergen
• 37-kDa protein
• Phospholipase A1 activity
• Also found in vespid venoms and belongs to
lipoprotein lipase family
• Some evidence of IgE reactivity against
protein determinants and showed some
cross-reactivity with yellow jacket, wasp
and honeybee venom phospholipase

Sol i 2 allergen
• 67% of total venom proteins
• Composed of two identical monomers, which have
3 intra- and 1 inter-molecular disulfide bonds
• Unique protein family: contain carbohydrate
determinants, disimilar to the other sol allergens
• Generate production of IgE antibody in about one-
third of individuals stung by fire ants
• Other similar venom proteins to Sol i 2: S.geminate
(Sol g 2), S.richteri (Sol r 2), S.saevissima (Sol s 2)

Sol i 3 allergen
• 24-kD protein, compromised of 20% of total
venom protein
• Demonstrate relationship to members of antigen 5
family of vespid venom proteins
• Overall structure is very similar to Ves v 5
• Relatively conserved some amino acid sequence
• But does not show cross-reactivity with vespid
venom antigen 5

Sol i 4 allergen
• Unique protein family
• Sol i 2 and Sol i 4 proteins have not
been found in other venoms and are not
similar to other known proteins
• Two proteins are related with each other,
but Sol i 4 lacks dimerizing cysteine
residues and present as monomer form
• Relate to S.geminate (Sol g 4) venom
Sol i 2 Sol i 4

Cross-reactivity
Phospholipase A1 group Group 2
Group 4
Antigen 5 group
Some cross reactivity
with vespids
• Similar structure but
no cross-reactivity to
antigen 5 group
• Sol i 3 and Sol r 3
78.2% homology
72.3% homology

Cross reactivity: among Solenopsis species
• Sol r 1 and Sol r 3 are similar to Soi i 1 and Sol i 3
• Sol r 2 allergen and Sol i 2 have less homology
• No allergen analogous to Sol i 4
• Serum from patients with reaction to stings by S.xyloni
were reactive to Sol i 1 and Sol i 3 but marginally
reactive to Sol i 2
• Limited data of allergic reactions from S.aurea
• Cross-reactivity between allergens of Sol i 1 and 3
have been reported
Formicidae
Solenopsis
(fire ant)
Myrmicinae
Family
Subfamily
Genus
Species

Formicidae
Solenopsis
(fire ant)
Myrmicinae
Family
Subfamily
Genus
Species
S.geminata (tropical fire ant)
• Composed of four venom proteins
• Sol gem 1: 37-kDa

S.geminata (tropical fire ant)
• Structures of four S.geminata venom proteins
appear to be similar to S.invicta allergens
• Amino acid sequence analysis exhibited a degree
of homology wih allergen of S.invicta and
probably similar allergenic properties
• Sol i 2 72.3% amino acid sequence
homology with Sol gem 2
Formicidae
Solenopsis
(fire ant)
Myrmicinae
Family
Subfamily
Genus
Species

•Some sequence differences between Sol 2 and Sol 4 antigens of fire ant
venom
•IgE antibodies against fire ant venoms are highly cross-reactive
•Reactions to stings from any fire any species can cause sensitization
to other species

Cross reactivity: between Solenopsis species and other ants
Pachycondyla
• Major cause of ant
hypersensitivity in Asia and
Middle East
• Controversial cross-reactivity
Mymecia
• Predominant cause of ant
hypersensitivity in Australia
• No evidence of cross-reactivity
between Myrmecia and fire ant
venom

Fire ant: limited or less
common to other venom
Golden DBK, et al. Annals of Allergy, Asthma & Immunology. 2017 Jan 1;118(1):28-54.
Cross reactivity: between Solenopsis
species and other hymemoptera

Clinical manifestation
Immediate reactions: occur within 1-4 hours after ant stings
• Normal local reactions: pain, swelling, erythema, heat and sterile pustules at
sting sites
• Large local reactions: reaction larger than 10 cm in diameter persisting for
longer than 24 hours
• Generalized cutaneous reactions: pruritus and urticaria
• Systemic reactions: anaphylaxis
Delayed reactions: usually occur more than 4 hours after ant stings
• Dermatitis, arthralgia, lymphadenopathy, renal abnormality, vasculitis

• 1-2 mm. pseudopustule secondary to alkaline pH
of complex alkaloids
• Result of toxic, cytolytic effects of venom
• Commonly distributed in clusters
• Insect instinctively bites with mandibles
• Sting multiple times in a radial pattern as it
moves its abdomen in an arc
Clinical manifestation: sterile pustules

• Localized reaction
• Immediate 2-5 cm. dermal flare
• Formation of wheal within 1 minute and papules within 2 hours
• Vesicles develop within 4 hours
• First, filled with clear fluid
• Then become cloudy à sterile pustules by 24 hours
• Pustule formation
• Superficial pustule is infiltrated with activated neutrophils and platelets with necrosis at base
at 24 hours
• Pustules develop within 24 hours of stings are are frequently confused with infectious
complications due to purulent apperance of vesicular fluid
Clinical manifestation: sterile pustules

Diagnosis
• Diagnosis of ant-induced hypersensitivity can be performed by documenting a
patient history of allergic reaction to ant stings
• History of circumstances of the sting
• Where it occurred, what the individual was doing, the nature of ant habitat
• Identification of causative ant should be determined by an entomological specialist
• Physical examination for evidence of ant stings
• Vital signs, respiratory and gastrointestinal signs and symptoms
• Carefully examined for evidence of anaphylaxis
• Skin lesions: pseudopustules at sting site within 24 hours

Diagnosis
•Useful clinical clues to diagnosis
•Development of typical pustule at sting site
•Species identification of the culprit insect
•Description of a typical fire ant mound in the vicinity of the sting
incident

Diagnosis
Honeybee Yellow jacket Wasp Fire ant
Tankersley MS, et al. The Journal of Allergy and Clinical Immunology: In Practice. 2015 May 1;3(3):315-22.

In vivo testing
•Skin testing using imported fire ant whole body
extract (WBE)
• Whole body extraction is the only reagent currently
available for diagnostic testing in patients with
suspected fire ant hypersensitivity
• WBE of other Hymenoptera contained insufficent
amounts of venom allergens
• WBE of imported fire ants has shown adequate
activity for diagnostic testing and immunotherapy
• Fire ant venoms are superior but have not been
practical to produce

• Fire ant whole body extracts
contain reduced concentrations of
relevant Sol i allergens by relatively
large amount of extraneous body
proteins
• Contain sufficient amounts of
venom allergens
• Currently available fire ant extracts
are not standardized
Stafford CT, et al. Annals of Allergy, Asthma & Immunology. 1996 Aug 1;77(2):87-99.
In vivo testing

• Patients: 33 adult patients with systemic allergic reactions to fire ant stings in past year without
history of other hymenoptera allergy
• Controls: 33 normal subjects living in a fire ant endemic area with no history of insec allergy
Skin test with IFA venom and 2 IFA WBE preparations
• SPT 1:1,000,000 wt/vol
• IDT 1:1,000,000 wt/vol to positive skin results
Objectives: to evaluate safety and effectiveness of IFA venom
compared with IFA WBE in diagnosis fire ant allergy
Stafford CT, et al. JACI 1992 Oct 1;90(4):653-61.

Results of skin testing
• Patients allergic to fire ants reacted to
protein concentrations in IFAV tenfold
lower than in IFA WBE
• IFAV is approximately 10 times more
potent than IFA WBE on protein content
• Patients reacted to lower concentrations
of all antigen preparation > controls
• No adverse reactions occurred to skin
testing with IFAV
• IDT with higher concentrations of IFA
WBE causes delayed large local
reactions in 16/30 (53%) control subjects
IFAV is safe, more potent than IFA WBE and may superior reagent for diagnosis of fire ant allergy
Stafford CT, et al. JACI 1992 Oct 1;90(4):653-61.

In vivo testing (skin test)
Reference SPT IDT
Practice parameter
2016
• If screening skin prick test response are negative, intracutaneous
testing should be performed
• Initial concentrations of 1:1,000,000 (1:1 million) wt/vol
• Increased by increments until a positive response is elicited or
maximum concentration of 1:1,000 or 1:500 wt/vol is reached
JACI in pract 2015 Concentration of
1:1,000 wt/vol
• Start with concentration of 1:1,000,000 wt/vol
• Progress in 10-fold increments until a positive skin test
response or maximum concentration of 1:1,000 wt/vol is reached
• No necessary testing with other stinging insect venoms if patient is able to identify fire ant
• Limited cross-reactivity between fire ant and other Hymenoptera

In vitro testing
• Serum specific IgE to imported fire ant venom
• Sensitivity is lower than skin testing
• 24% of non-allergic cases have positive specific IgE test results for imported fire ant
venom
• High degree of asymptomatic IgE production in exposed population
• Skin testing and serum specific IgE should not performed without a
clinical history of allergic reactions

• Patients: 32 patients with history of ant
anaphylaxis and positive specific IgE or skin
testing
• Control: 14 healthy subjects who had history
of fire ant sting without any symptoms or only
small local reaction
Most common species: Solenopsis geminata
Skin test
positive 10/17
sIgE positive 7/13

12 patients
• Positive skin test 8/9 (88.9%)
• Positive sIgE to IFA extract
10/12 (83.3%)
14 controls
• Negative results for serum-
specific IgE to IFA

Fire ant allergen profile and specific IgE reactivity
• TFA extract >20 bands
of protein 10-200 kDa
• IFA allergens 2 major
bands 25-35 kDa
IFA: only weak IgE reactive
bands at 26 and 55 kDa

Fire ant allergen profile and
specific IgE reactivity
• Major allergen of TFA ,
S.geminata, present 80% of ant
allergic patients’ serum: 26, 55
and 75 kDa
• Weak IgE reactive to S.invicta
from Thai ant anaphylaxis to 26
and 55 kDa protein
• Cross-reactive IgE by 26,55 kDa

In house TFA WBE ELISA
• Patients: all 12 patients displayed sIgE to
S.geminata allergens and significantly
higher than sIgE in healthy controls
• Controls: 2 positive IgE-ELISA tests (false
positive 2/14, 14.3%)
• TFA extract is more sensitive than IFA
extract for identification and diagnosis of
ant hypersensitivity patients in Thailand

Ant-sting challenge test
• Used for patient with history of ant anaphylaxis but negative skin testing and
serum specific IgE results
• Not recommended as a routine diagnosis and not used extensively
• Increase change of provoking serious allergic reaction
• Specialized centers are required for sting challenge

Management of ant-induced hypersensitivity
Clinical manifestation Treatment
Local reaction • Local wound care
• Wound dressing
• Topical or systemic antibiotics for secondary infection
• Cold compression to reduce local swelling
• Topical corticosteroid to limit the swelling of large local reaction
• Pseudopustules from fire ant stings shoule be kept clean and intact to
prevent secondary bacterial infection
Systemic reaction • Acute management of anaphylaxis

Prevention
Preventive measure: immunotherapy and re-sting avoidance
• Not disturbing ant nests
• Pest control and elimination of ant
nests from home areas
• Allow nests to be removed by
trained professionals
• avoid walking barefoot or with
sandals
• Wear long pants and long-sleeved
shirts when working outdoors

Venom immunotherapy

• VIT is still an
acceptable option if
there are special
circumstances
• History of
unavoidable
cutaneous systemic
reaction or LLR,
frequent exposure,
lifestyle considerations
• Weight against added
cost and potential
inconvenience
Venom immunotherapy

• Use skin tests as the preferred
test for initial demonstration of
venom-sIgE
• sIgE used as complementary
or alternative test
• Test for all 5 venoms
• Possible exception of individual
patients in whom a single
culprit is definitively known
Venom immunotherapy

• In vitro venom testing should be
performed in patients with negative
skin test and be potential
candidates for VIT
• Postpone testing until 3-6 weeks
after sting reaction
• Reduced sensitivity within first few
weeks after reaction
Venom
immunotherapy

• Consider measuring basal serum
tryptase in all patients who are
candidates for VIT
• Increased risk of severe anaphylaxis to
stings before, during and after VIT
Venom
immunotherapy

High risk factors
• Very severe reaction before VIT:
syncope, hypotension, severe
respiratory distress
• Systemic reaction during VIT
• Honeybee allergy
• Increased basal serum tryptase levels

Sturm GJ, et al. Allergy. 2019 Oct;74(10):2016-8.

Alvaro-Lozano M, et al. Pediatric Allergy and Immunology. 2020 May;31:1-01.

Immunotherapy
• Considered for adults and children with systemic reactions to ants + positive results by
skin testing or specific IgE antibodies
• Same recommendation as the immunotherapy recommemed for hymenoptera
hypersensitivity
• Children with isolated cutaneous systemic reactions from ant stings do not require
immunotherapy due to low risk of subsequent systemic reactions
• Children with significant exposure risk may be considered for treatment with imported fire ant
immunotherapy
• Insufficient data on efficacy of immunotherapy for ant species other than imported fire ant

Immunotherapy
Practice parameter 2016

Immunotherapy
• Dosage schedulle for fire ant WBE immunotherapy is less well defined in terms of
rapidity of buildup
• Most authors recommend a once- or twice-weekly buildup schedule
• Until a maintenance dose is reached, the interval between doses can then be
increased
• Most reports recommened maintenance dose of 0.5 ml of 1:100 wt/vol
• Some recommended a dose as high as 0.5 ml of 1:10 wt/vol extract

• Population: all patients with history of anaphylaxis
to IFA sting and positive skin test to IFA
• Objective: to examine the effectiveness of WBE
immunotherapy for IFA hypersensitivity
• Comparison 65 patients on immunotherapy VS
11 patients without immunotherapy
• Sting challenge: 30 volunteers of 65 patients on
immunotherapy
76 patients with Hx anaphylaxis
and SPT positive to IFA
65 patients agreeed to
start immunotherapy
11 patients declined
immunotherapy
31 patients on
maintenance IT
4 patients no
immunotherapy
30 patients consented to undergo
a controlled sting challenge
Agreed to additional testing
• SPT: 1:1,000 wt/vol
• IDT 1:1,000,000 to 1:1,000
Maintenance IT 0.5 ml of 1:100 wt/vol
Freeman TM, et al. JACI 1992 Aug 1;90(2):210-5.

Results: comparison immunotherapy VS untreated group
Subsequent
sting reaction
Sting challenge: 30/65 patients à only local reactions
Immunotherapy
• Duration 6 month to
18 years
• Maintenance dose of
0.2-0.5 ml of 1:20 to
1:100 wt/vol

Result: skin testing
• 26 (84%) à negative skin test
• 5 (16%) à positive at lower dilution than initial testing
4 (100%) à persistent positive skin test

Effectiveness of IFA-WBE VIT
• IFA-WBE is effective in decreasing incidence of anaphylaxis during subsequent field
stings
• Reduce specific IgE as demonstrated by skin test
• Protect against systemic reactions provoked by a sting challenge with a single IFA
• However, no placebo-controlled trials support IFA-WBE VIT

Effectiveness of IFA VIT
Only 2.9% (4/137) systemic
reaction due to VIT
Adverse reactions
Efficacy and sting challenge
85.7% (24/28)
no worse than LLR
Park HJ, et al. Journal of Allergy and Clinical Immunology: Global. 2022 Apr 15.

Immunotherapy: rush protocols
IFA sting incidence is high in endemic areas à rapid
attainment of maintenance immunotherapy dose is desirable
Steigelman DA, et al. Annals of Allergy, Asthma & Immunology. 2013 Oct 1;111(4):242-5.

Safety and efficacy of IFA rush protocol
• Population: patients aged 18-65 years with IFA
hypersensitivity
• History of systemic reaction to IFA sting
• Presence of positive IFA skin test
• Objective:
• Investigate safety and efficacy of rush
immunotherapy with IFA WBE
• Determine whether prophylactic pretreatment
with antihistamine and steroid reduced
systemic reaction rate
59 patients with IFA hypersensitivity
28 Premedication group 31 Placebo group
Twice-daily 2 days before RIT
• Terfenadine 60 mg
• Ranitidine 150 mg
• Prednisolone 30 mg
Rush protocol immunotherapy
Efficacy on day22: sting challenge
Double-blinded randomization
Tankersley MS, et al. JACI. 2002 Mar 1;109(3):556-62.

59 patients with IFA hypersensitivity
56 patients completed rush IT
and sting challenge
3 patients withdrawn from study
• 2 patients SRs
• 1 patient SE of prophylaxis
medication (placebo)
Safety and efficacy of IFA rush protocol

• Safety: 3/58 (5.2%) patients with systemic reactions during RIT (2 on placebo, no significant)
• Sting challenge: 1/56 (1.8%) treatment failure, 55/56 (98.25) efficacy rate
• Rush protocol with IFA WBE is safe and effective. Premedication is not necessary.

Safety of IFA rush protocol
To present 3 cases of patients with 36 months or younger
completed a 1-day rush immunotherapy protocol with IFA-WBE
Age 30 months Age 22 months Age 36 months
Judd CA, et al. Annals of Allergy, Asthma & Immunology. 2008 Sep 1;101(3):311-5.

Safety of IFA rush protocol
• No systemic reactions occurred
during 1-day RIT
• All 3 patients experienced mild local
reactions at injection sites
• No modifications of 1-day RIT protocol
schedule
• Case series provides data of efficacy
and safety of a 1-day IFA RIT protocol
for prevention anaphylaxis
Judd CA, et al. Annals of Allergy, Asthma & Immunology. 2008 Sep 1;101(3):311-5.

• Retrospective chart review
• Population: all pediatric patients on rush
immunotherapy with ant whole body extract
• History of anaphylaxis caused by ants with
• Evidence of IgE sensitization to ants: SPT, sIgE
3-day RIT protocol
• Premedication: H1 antihistamine
• Monitor safety of RIT procedure
based on WHO grading system
• Efficacy: reactions after a field
ant re-sting
Manuyakorn W, et al. APJAI. 2017 Sep 1;35(3):156-60.

• Weekly until reach maintenance dose
• 4-week intervals for 18 months then 6-week interval for 18 months then 8-week intervals

All of patients reached the maintenance
dose of 0.5 ml of 1:100 wt/vol of ant
(Solenopsis invicta) after initiation

No significant difference
• 4 children developed
grade 3 systemic reactions
• Resolved after increasing
maintenance dose to
0.5 ml of 1:50 wt/vol

Immunotherapy: effectiveness
• Maintenance dose of 0.5 ml of 1:100 wt/vol of Solenopsis invicta immunotherapy
60% efficacy for preventing a field ant re-sting
• 4 children with systemic reactions after the maintenance dose increased to 0.5 ml of
1:50 wt/vol à no further systemic reactions upon ant re-sting (100% efficacy)
• Solenopsis invicata is not the common species in Thailand
• Solenopsis geminata, Tetraponera rufonigra and Odontoponera denticulata are
common invasiec ant species with important role on clinical hypersensitivity
3-day ant RIT procedure is safe, tolerable and effective in children

Testing cross-reactivity
• Potiwat, et al: 12 patients with allergy to
S.geminata were evaluated for cross-reactivity to
S.invicta
• Positivity of specific IgE levels to IFA extract
(S.invicta) was found in 83.3% and skin test was
positive in 88.9%
• Serum S.invicta-specific IgE: lower sensitivity
than skin test
• Major reactive proteins IFA extract (S.invicta):
similar molecular weight 26 and 55 kDa to major
allergens of S.geminata
• Possibility of cross-reactivity of patient’s serum-
specific IgE (S.invicta and S.geminata)
AAAAI: Ask The Expert
AAAAI

Treatment effectiveness
• Manuyakorn et al, demonstrated that standard
dosage of 0.5 ml of 1:100 wt/vol of S.invicta
used as immunotherapy for S.geminata
anaphylaxis in Thai patients
• Only 60% efficacy for preventing a field
ant re-sting
• After increasing dosage to 0.5 ml of 1:50
wt/vol: efficacy increased to 100%
AAAAI: Ask The Expert
AAAAI
• Provide evidence of cross-reactivity between S.geminata and S.invicta for both
testing and therapy
• Increase maintenance dose to 0.5 ml of 1:50 wt/vol provides greater protection

Immunotherapy: duration
Duration: optimal duration is less well defined

Reference Duration Lifelong VIT
BSACI 2011 3 years • During VIT, still has reaction
• After VIT, continue risk of multiple stings
• Elevated baseline serum tryptase or mastocytosis
Practice parameter
2016
3-5 years (prefer 5 years) • History of severe reaction
EAACI 2018 3-5 years (prefer 5 years,
severe initial sting reactions)
• Bee venom allergy with frequent unavoidable exposure
• Very severe initial reactions
• Systemic side effectes during VIT
Children user’s
guide 2020
3-5 years (prefer 5 years) -
Immunotherapy of hymenoptera: duration

Reference Duration Lifelong VIT
Middleton 9th
edition
May be stopped after 5 years Cited practice parameter 2016
• History of severe reaction
Clinical immunology • Lifelong treatment may be
safest recommendation
• Most center, VIT is given
for up to 5 years
• Cutaneous or systemic mastocytosis
• Longer duration in high-risk patients
• Very severe systemic sting reaction
• Coexisting cardiovascular or pulmonary disease
• Systemic allergic reactions to VIT or stings during VIT
Immunotherapy of hymenoptera: duration

Immunotherapy: Adverse reactions
• Overall incidence of systemic adverse reactions to VIT 5-40%
• Same as other forms of allergen immunotherapy
• Mild reactions, <5% require epinephrine treatment
• Premedication
• Antihistamine
• Reduce LLRs and mild systemic reactions but not suppress severe SRs
• Antihistamine 2 hours before up-dosing injections until maintenance dose well tolerated
• Consistency use or avoid antihistamine for appropriate interpretation of reactions
• Leukotriene modifier: reduce LLRs
• New vial, changing manufacturer: reduce dose 20-50%
• Carrying epinephrine autoinjector in high-risk SRs Middleton’s allergy 9th edition. 2020

• Reaction during build-up: reduce allergen dose (1-2 steps back)
• Premedication with H1 antihistamine
• Omalizumab: SRs prevent reaching maintenance
Venom immunotherapy: Adverse reactions
Sturm GJ, et al. Allergy. 2018 Apr;73(4):744-64.

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