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Disease Summaries

Allergy to Insect Stings and Bites

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Posted: November 2008

A/Prof Robert (Bob) Heddle MBBS, PhD, FRACP, FRCPA
Head of Clinical Immunology
Royal Adelaide Hospital and Institute of Medical and Veterinary Science
Adelaide, South Australia

David B.K. Golden, M.D.
Associate Professor of Medicine
Johns Hopkins University
Baltimore, Maryland, USA

Scope of Article

This article is limited to discussion of reactions to insect stings and bites. In most regions, the former dominate and will be the prime topic here. This article does not deal with other allergic reactions to inhaled or ingested insect components or products.

Definitions

Sensitization to insect venom refers to the presence of specific sensitivity to insect venom, most commonly mediated by IgE and demonstrable by skin testing or in vitro assay.

Allergy to insect venom refers to a clinical reaction to one or more stings that is greater than would be expected in the general population and results from specific sensitization to that venom.

Symptoms and Signs

Most individuals will develop limited local swelling in response to a sting that is of nuisance value. A minority of persons will develop excessive local swelling, which may be either "immediate" (developing and peaking within 1-2 hours) or "delayed". Such events only threaten life if in close proximity to the airway.

A small percentage of the population develops "systemic" or "generalized" reactions that extend beyond areas contiguous with the sting. Most of these are immediate IgE-mediated allergic reactions and show the same range of features as other such reactions. These include cutaneous, mucosal, respiratory, cardiovascular, gastrointestinal and/or neurological involvement (see table 1). Systemic reactions have commonly been classified with the use of the four stage system of Ulrich Müat;ller, a modification of the system of Harry Müat;ller. More recently, Simon Brown proposed a three tier system (table 1) that is based on evidence as to which features correlate with the development of hypoxia and/or hypotension. Hypotension appears to be more prominent in severe reactions to insect stings than in allergic reactions to foods. This may reflect the tendency of severe sting reactions to involve older subjects. Systemic allergic reactions of rapid onset with lethal potential (e.g. those with respiratory or vascular compromise) constitute "anaphylaxis". Rarely, stings can cause other unusual manifestations that are more likely to be toxic than hypersensitivity reactions.

TABLE 1. Grading system for generalized hypersensitivity reactions

Grade Defined by
1 Mild Skin and subcutaneous tissues only* Generalized erythema, urticaria, periorbital edema or angioedema
2 Moderate Features suggesting respiratory, cardiovascular or gastrointestinal involvement Dyspnea, stridor, wheeze, nausea, vomiting, dizziness (presyncope), diaphoresis, chest or throat tightness or abdominal pain
3 Severe Hypoxia, hypotension or neurologic compromise Cyanosis or SpO2 < 92% at any stage, hypotension (SBP < 90 MM Hg in adults), confusion, collapse, LOC or incontinence

SBP, systolic blood pressure; LOC, loss of consciousness.

*Mild reactions can be further subclassified into those with and without angioedema

Reproduced with permission from Brown SGA, J Allergy Clin Immunol 2004 (114): 371-6.

Epidemiology and Etiology

Estimates of the prevalence of subjects who have experienced immediate systemic reactions to insect stings vary from 1% to 7% of the general population. The insects that account for the problem vary by region. The honey bee is ubiquitous, yellow jackets (Vespula) cause sting allergy problems across diverse temperate climates and paper wasps (Polistes) and in some regions hornets (Vespa) tend to be important at lower latitudes. Stinging ants are more restricted in their distribution, but the imported fire ant (Solenopsis invicta) and jack jumper ant (Myrmecia pilosula spp) dominate clinical sting allergy in areas of South Eastern-South Central USA and South Eastern Australia, respectively, whereas species of Pachycondyla are major public health problems in East Asia and the Arabian Peninsula.

Although immediate systemic reactions to insect bites are less common, anaphylaxis to biting insects like kissing bug (Triatoma), horseflies (Tabanus spp), mosquitoes (Aedes, Culex, Anopheles) has rarely been reported.

Estimates of the number of deaths from sting anaphylaxis vary around 1 per 10,000,000 per annum, but this figure is likely to be an underestimate and to vary widely regionally.

Referral and Diagnosis

Accurate diagnosis is essential because it has long-term consequences, including provision of an adrenaline auto-injector, long-term venom immunotherapy and, in some cases, change in occupation or relocation. It requires knowledge of the entomology of the region, of the natural history of the sting allergy (see below) and of the availability and limitations of the skin and in vitro tests for venom allergy. Referral to an experienced allergy specialist is strongly recommended.

Diagnosis must be made at several levels:

  1. The nature of the subject's worst insect sting reaction. An accurate history of the worst sting reaction is essential because it is important in predicting future risk (see the section "Natural History and Risk Assessment" below). Clinical responses to stings are variable events, and the clinician should be guided by the subject's worst reaction to the insect. If possible, case records should be reviewed for objective manifestations, but it must be borne in mind that some subjects may have been more severely compromised before reaching medical care.
  2. The probable identity of the responsible insect. Features to consider when identifying the insect include observations made at the time of the sting, the place and circumstances of the sting (e.g. proximity of garbage or food favors the yellow jacket, native bushland in South East Australia favors the jack jumper ant), the presence or absence of a stinger in the skin (the presence favors the honey bee, Apis mellifera or among vespids, Vespula maculifrons), past sting history and any culprit specimen presented. The season of the sting event may be helpful in moderate climates: honey bee stings occur most often in spring and summer, vespid stings mostly during late summer and fall.
  3. Skin test or in vitro evidence of IgE sensitization of the subject to relevant venoms. Specialist expertise is required because of the limitations in availability and sensitivity of both skin and in vitro tests for venom-specific IgE. Testing should be carried out with venoms of all likely insects. Even where sensitivity of both is high (of the order of 97% with honey bee venom), both skin and in vitro tests and a repeat skin test 3 months later should be negative before it is concluded that the subject lacks demonstrable specific IgE to the venom. This is more strongly the case where sensitivity and specificity of both tests are lower (e.g. 68-86% for yellow jacket venoms). Venom skin testing necessitates satisfactory positive and negative controls and a positive response to intradermal testing at 1 microgram/ml or less (Bilo, Rueff, Mosbech et al, 2005). Such testing can precipitate a systemic allergic reaction, however, and expertise and facilities for resuscitation should be immediately available.
  4. Other in vitro tests. Mast cell tryptase levels measured within 30 minutes to 8 hours after the onset of the index reaction may if raised support the conclusion that the reaction features resulted from an allergic reaction; however, a negative test result does not exclude that possibility. Comparison of the acute with a convalescent specimen may increase sensitivity. If baseline mast cell tryptase is raised, the subject may have a systemic mast cell disorder (see the section "Management of co-morbidities" below). In vitro tests measuring activation of surface markers of basophils or release of mediators from these cells after addition of the allergen, may be helpful in individual patients with a strong history of sting anaphylaxis but negative skin tests and no detectable serum IgE to venoms.
  5. Sting challenges. These are the gold standard for clinical sensitivity in research, but have a limited place in clinical practice because of substantial risks of anaphylaxis and of either false-negative responses or sensitization to future stings, especially if performed in untreated patients. They should only be undertaken when there is a strong indication for the procedure, high-level facilities and expertise, informed consent and institutional ethics committee approval. In most European countries sting challenges are only performed for the confirmation of efficacy during venom immunotherapy.
Apis mellifera

(1) Apis mellifera (honey bee)

Bombus spp.

(2) Bombus spp. (Bumble bee)

Vespula germanica

(3) Vespula germanica ("yellow jacket," "European wasp," or "common wasp")

pictures relating to M.pilosula

(4) Compound of pictures relating to M.pilosula

M.pilosula
Myrmecia pyriformis

(5) M.pilosula (jack jumper ant)
(6) Myrmecia pyriformis (a common "inch ant" or "bulldog" ant)

Photos By: A/Prof SGA Brown

Natural History and Risk Assessment

Humility is appropriate in approaching this topic for two reasons: first, many subjects dying of apparent allergic reactions to stings have no known history of an earlier systemic reaction and second, sensitization to insect venoms is much more common than is clinical allergy to the same insect venoms. Further, any prediction of risk based on published studies cannot be extrapolated with confidence to a specific patient. Nevertheless, from epidemiological and deliberate sting study outcomes, the following strong trends are apparent:

  1. Subjects who have experienced only enhanced local or even generalized cutaneous reactions run a relatively low risk, of the order of 5-20%, of a systemic reaction, which is usually of limited severity, to a subsequent sting by an insect of the same species.
  2. A previous severe systemic reaction and, in particular, hypotensive anaphylaxis indicates a high risk (50-70%) of a further severe reaction.
  3. Risk of a severe or lethal reaction appears to rise with increasing age
  4. In deliberate sting studies, higher proportions of subjects who have had recent systemic allergic reactions to jack jumper ant or honey bee stings have had a similar reaction to their next sting compared with yellow jacket-allergic subjects (respective figures are approximately 72%, 52-75% and 25-40%). Such outcomes will vary with the age of subject, the severity of the index sting reaction and possibly the time elapsed since the last sting.
  5. Positive tests for IgE to venom increase the risk of a systemic reaction to a sting, and even asymptomatic, sensitized subjects carry a significant but low risk (circa 17%). However, except for allergy to jack jumper ant venom, the degree of skin test reactivity appears to be a poor predictor of reaction severity.

Factors that appear common in forensic cases are remote rural occupations or recreation, cardiorespiratory co-morbidities or possibly treatments for vascular disease (such as beta blocking drugs and ACE inhibitors)

Management

Acute treatment

The reader is directed to WAO Allergic Disease Resource "Anaphylaxis: Synopsis" for a review of anaphylaxis and its management, the Updated Practice Parameter on management of anaphylaxis (2005) and WAO statement on use of epinephrine (2008). (refer references). Adrenaline is the key medication in managing anaphylaxis. Although there is strong evidence for the efficacy (and in expert hands, safety) of adrenaline infusion from a large prospective study of reactions to deliberate jumper ant stings, the simple procedure of injecting appropriate doses of adrenaline IM into the anterior thigh is recommended for prompt initiation of effective therapy with a high margin of safety. (refer consensus statements as above). Administration of high-flow oxygen and airway support and in hypotensive subjects a horizontal, legs-elevated posture and rapid infusions of IV fluids through a large-bore cannula are recommended. For life-threatening reactions, emergency support should be summoned because further measures might be required that necessitate special expertise (e.g. intubation, tracheostomy or use of selective vasopressor medications). There appears to be no reliable way of predicting biphasic anaphylaxis or its timing. Participants in the second NIAID/FAAN symposium on anaphylaxis recommended that observation times be individualized on the basis of the severity of the initial reaction, reliability of the patient and access to care.

Emergency plans and adrenaline auto-injectors

Subjects with a history of an immediate systemic reaction to a sting need a written plan that includes the following: symptom recognition, guidelines for summoning assistance, indications for and method of use of automated adrenaline syringe and indication that urgent transport to emergency care and at least four hours of observation at the point of care after symptom resolution are required. Such plans must take account of regional factors and past reactions, including speed of evolution and severity. Prospective sting studies suggest that some adults require provision of and guidelines for use of a second automated adrenaline syringe, depending on anticipated reaction severity and distance from care. Published data indicate that compliance with carriage, maintenance and use of automated adrenaline syringes is often disappointing, which underscores the need for careful instruction, periodic retraining and emphasis that other medications do not represent alternatives to the use of adrenaline except for the mildest of systemic reactions (e.g. slowly evolving reactions confined to the skin). However, small doses of adrenaline are not contraindicated in these cases.

Management of co-morbidities

It appears probable that cardiovascular and respiratory co-morbidities contribute to the risks of an adverse outcome. Treatment of such conditions should be optimized in consultation with other health care professionals. A particularly difficult issue arises when a subject has indications for medications such as beta blocking drugs or ACE inhibitors that may potentiate anaphylaxis or complicate its management. Bearing in mind that there is no systematic evidence that these medications increase risk of severe anaphylaxis, a team approach is required that weighs the relative risks of each condition and the risks and benefits of each medication.

Identification of subjects with raised baseline mast cell tryptase is important because such subjects are disproportionately at risk of severe reactions to multiple stimuli, including insect stings. Please refer to following section on venom immunotherapy.

Venom immunotherapy

Insect VIT is a potent tool for preventing sting anaphylaxis. Controlled studies demonstrate that immunotherapy with vespid, honey bee and jack jumper ant venoms are highly effective. Once subjects are receiving maintenance doses of yellow jacket or jumper ant venom, the risk of an immediate generalized reaction to a sting is approximately 5% per sting. Honey bee VIT is less effective by that criterion (the risk of a generalized reaction is of the order of 20% per sting), but needs to be assessed against an adverse natural history without immunotherapy. Many of the documented "failures" have involved mild systemic reactions.

Although a statistical assessment of the effect of VIT on the risk of death is difficult if not impossible, studies in yellow jacket-sensitive subjects have shown a marked improvement in quality of life.

Problems with VIT include the following:

  1. Selection of subjects and co-morbidities. Any subject with a history of a systemic allergic reaction to a sting and evidence by skin testing or in vitro tests of specific IgE to that venom should be considered for VIT. There is not yet evidence to support the use of VIT in asymptomatic sensitized subjects or in subjects who have experienced systemic reactions but lack evidence of IgE to the venom. There is recent evidence that VIT can reduce the tendency to excessively large local reactions, but given costs and morbidity, use of VIT for this purpose should be highly selective. Subjects whose co-morbidities or treatments might render them at high risk of adverse VIT outcomes may be the subjects most at risk when left untreated and special considerations beyond the scope of this general review apply to this group (refer M?ller and Haeberli, 2005). Elevated baseline serum tryptase or definite systemic mastocytosis are associated with an increased risk of side effects during venom immunotherapy and of relapses after stopping it. Four fatal sting reactions have been reported after stopping venom immunotherapy. Three occurred in patients with documented systemic mastocytosis, in the fourth mastocytosis, was not considered in the differential diagnosis. For this reason, VIT in patients with systemic mastocytosis is recommended for life (Mueller, 2007).
  2. Regimens. The most rigorous trials have used regimens in which incremental doses are given in ambulatory care at approximately weekly visits, either several doses per visit ("clustered" or "semi-rush") or single doses per visit or a mixture of the two. "Ultra-rush," in-hospital regimens, take patients to maintenance doses over 1-2 days or to near maintenance doses over 4 hours. Such regimens are now widely used because they appear to offer greater convenience and accelerated achievement of the target maintenance dose. With VIT to yellow jacket, such regimens appear also to have safety advantages, but whether this pertains to other venoms, which engender higher reaction rates during VIT, is problematic.

    Similarly, the selection of monthly 100-microgram maintenance doses for vespid, honey bee and jack jumper ant VIT has been empirical. Some subjects benefit from doses as low as 50 mcg, whilst others require doses of 250 mcg. Many subjects who tolerate their monthly maintenance doses can have progressive extension of the interval for maintenance injections to every 6-8 weeks. Although selected subjects who tolerate VIT may be treated every third month, the rate at which it should be attempted and its effect on long-term outcomes remains open to question.
  3. Morbidity. Within published trials and large-scale prospectively defined studies, 10-40% of subjects have experienced systemic allergic reactions to VIT. Within that range, yellow jacket venom gives fewer reactions than does bee or jumper ant VIT. Whilst most reactions fall short of anaphylaxis, the risks are sufficient to warrant limitation of immunotherapy to personnel and centers expert in the procedure and at recognizing and treating anaphylaxis and to situations of fully informed consent.
  4. Duration. Suggested endpoints to VIT include reversion of venom skin tests and in vitro tests for venom-specific IgE to negative and/or 5 years of well-tolerated maintenance VIT. However, the first is achieved within 5 years in only a minority of subjects. Furthermore, once immunotherapy ceases, there is a risk of relapse of clinical sensitivity that has been estimated at around 10% per sting. After two decades, the reactivity of the post-VIT population approximates that of sting-allergic subjects who have not had further venom exposure. Approaches to this problem include continuing VIT indefinitely in high-risk subjects and ongoing carriage of an adrenaline auto-injector.
  5. Development of VIT. Measures that would facilitate VIT or reduce its morbidity would be valued. There are reports of use of IL-10 or of alum adjuvant for this purpose and a few case reports in which omalizumab (monoclonal, humanized anti-IgE that binds IgE at the Fc epsilon R1 binding site, thus preventing participation in mast and basophil triggering) was used in difficult cases to facilitate VIT. The broader applicability and cost-effectiveness of these approaches needs to be studied.

    Circumstantial evidence exists that in contrast with the experience with vespids, honey bees and jack jumper ants, whole-body extracts of imported fire ant may be effective, presumably because they contain sufficient venom. Nevertheless, a rigorous comparison with a venom extract appears warranted.

There are cost problems with provision of venoms for some Hymenoptera species, either because of limited distribution (e.g. jack jumper ants, some paper wasp species) or very small quantities of venom available from each insect (e.g. imported fire ant). Experimental work is underway with recombinant allergens for diagnosis and therapy.

Prevention

At an individual level, reasonable measures include minimization of situations that attract the responsible insects (e.g. garbage, uneaten food for yellow jackets and perfumes for honey bees) and use of protective footwear and clothing. At a community level, many of the sting allergy problems have an ecological basis, such as introduction of the imported fire ant into the USA where natural controls are lacking and decline of native predators (echidnas) of the jack jumper ant and intrusion of housing into the ants' natural habitat.

References

General reviews

Graft DF. Insect sting allergy. Med Clin North Am 2006;90:211-32.

Bonifazi F, Jutel M, Bilo BM, Birnbaum J, M?ller U, EAACI. Prevention and treatment of Hymenoptera venom allergy: guidelines for clinical practice. Allergy 2005;60:1459-70.

Golden DBK. Insect sting allergy and venom immunotherapy: A model and a mystery. J Allergy Clin Immunol 2005;115:439-47.

Freeman TM. Hypersensitivity to Hymenoptera stings. N Engl J Med 2004; 351:1978-84.

Reviews of ant sting allergy

Klotz JH, deShazo RD, Pinnas JL, et al. Adverse reactions to ants other than imported fire ants. Ann Allergy Asthma Immunol 2005;95:418-25.

Brown SGA, Heddle RJ. Prevention of anaphylaxis with ant venom immunotherapy. Curr Opin Allergy Clin Immunol 2003;3:511-6.

References regarding anaphylaxis

Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: Summary Report- Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Ann Emerg Med 2006;47:373-80.

Lieberman P, Kemp SF, Oppenheimer JJ, et al. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 2005;115(suppl):S485-S523.

Kemp SF, Lockey RF, Simons FER, on behalf of the World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis. Epinephrine: The drug of choice for anaphylaxis - a statement of the World Allergy Organization. WAO Journal 2008;S18-S26

Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-6.

Key trials of venom immunotherapy

Brown SGA, Wiese MD, Blackman KE, Heddle RJ. Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial. Lancet 2003;361:1001-6.

Hunt KJ, Valentine MD, Sobotka AK et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61.

Diagnostic methods

Bilo BM, Rueff F, Mosbech H et al. Diagnosis of Hymenoptera allergy. Allergy 2005;60:1339-49.

Golden DBK, Kagey-Sobotka A, Norman PS et al. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol 2001;107:897-901.

Venom immunotherapy in presence of co-morbidities

Müat;ller UR, Haeberli G. Use of β-blockers during immunotherapy for Hymenoptera venom allergy. J Allergy Clin Immunol 2005;115:606-10.

Mueller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol 2007; 7:337-41

Comment: In this paper there is also a discussion of mastocytosis and venom allergy based on a case presentation by David Golden.