Clinical Review ABC of allergies

Venom allergy

BMJ 1998; 316 doi: http://dx.doi.org/10.1136/bmj.316.7141.1365 (Published 02 May 1998) Cite this as: BMJ 1998;316:1365
  1. Pamela W Ewan

    Stings from bees and wasps, the most common stinging insects in Britain, can cause severe allergic reactions, including anaphylaxis. Coroners' data suggest that an average of four deaths from bee or wasp stings occur each year in the United Kingdom, but this is almost certainly an underestimate because venom anaphylaxis is not always recognised as the cause of death.

    Figure1

    Honey bee (Apis mellifera): 1.5 cm long, fairly hairy and brown with abdominal bands

    Hymenoptera insects

    Classification

    The hymenoptera are subdivided into families, including the Apidae (honey bees and bumble bees) and the Vespidae (wasps, hornets, and paper wasps). In Britain most reactions are caused by stings from wasps (the Vespula species) rather than from bees. Reactions to bee stings are almost always associated with the honey bee.

    Venoms

    Bee and wasp venoms are different, each containing distinct major allergens, which are well defined. Phospholipase A2 and mellitin occur only in bee venom, and antigen 5 only in wasp venom, but both venoms contain hyaluronidases. Patients allergic to wasp venom are rarely allergic to bee venom.

    Figure2

    Wasp, also known as yellow jacket (Vespula spp): ≤1.5 cm long; yellow and black striped abdomen; typical waist; and little hair

    Sensitisation

    Most people, unless they have a specific occupational risk, are rarely stung by wasps, perhaps once every 10-15 years. Sensitisation to wasp venom requires only a few stings, and can occur after a single sting.

    In contrast, allergy to bee venom occurs mainly in people who have been stung frequently by bees. Thus almost all patients who are allergic to bees are beekeepers or their families, or sometimes their neighbours.

    Clinical features

    The normal effect of a bee or wasp sting is to cause intense local pain, some immediate erythema, and often a small area (up to 1 cm diameter) of oedema. Allergic reactions can be either local or generalised.

    Figure3

    Patient with angio-oedema of the left forearm: local allergic reaction to a bee sting

    Local reactions

    Local reactions involve oedema at the site of the sting. This comes on over several hours and varies in size, but it can affect a hand or even an entire limb. In a dependent area this can lead to blistering and sometimes secondary infection. Such oedema is not dangerous unless it affects the airway.

    Generalised reactions

    Generalised (or systemic) reactions vary greatly in severity. Early features are erythema and pruritus, followed by urticaria and facial or generalised angio-oedema. Patients with more severe generalised reactions often feel extremely ill, as if they are going to die (“a sense of impending doom”). Dyspnoea often occurs and can be due either to laryngeal oedema or to asthma. In severe reactions hypotension occurs, causing lightheadedness, giddiness, fainting, or loss of consciousness. Other less common features are abdominal pain, incontinence, central chest pain, or visual disturbances.

    Figure4

    Patient with angio-oedema and blistering of the ankle: local allergic reaction to a bee sting

    The clinical picture is variable—patients may have only erythema, urticaria, and angio-oedema or may develop loss of consciousness, with few warning symptoms, within minutes of a sting. The onset of generalised reactions is early, usually within 10 minutes of a sting.

    Diagnosis

    Venom allergy is diagnosed from the history of the allergic reaction, backed up by tests for venom-specific IgE antibodies. It is important to check the basis of the patient's assertion about the type of insect responsible for the sting. Many patients say the sting is from a bee when it is in fact a wasp sting. The vast majority of patients (except beekeepers etc) will be wasp allergic. Accurate diagnosis is important as it has implications for management.

    Natural course

    • A substantial proportion of patients (20-80% in different studies) with a history of a generalised reaction to a sting have no such reaction to a subsequent sting—that is, spontaneous improvement is common

    • Less severe generalised reactions may also occur

    • However, the course can be variable—a series of stings may result in a generalised reaction, no reaction, and then another generalised reaction

    • Children do particularly well: one study showed that 95% of those with a history of mild generalised reactions had no reaction to a subsequent sting

    • The next sting will not necessarily cause a more severe reaction, but patients in accident and emergency departments are often told that it will

    • Reasons for the variable outcome are not well understood but include the interval from the last sting (the longer the interval the lower the risk of another generalised reaction), the patient's immune response at the time of the sting (this will change with time), the dose of venom injected, and the site of the sting

    The history should be confirmed by demonstrating, by skin test or blood test, specific IgE; this is essential if desensitisation is considered as a treatment. Skin tests—either skin prick tests or intradermal tests with bee and wasp venom and the appropriate positive and negative controls—are more accurate but should be done by allergists as skin tests for venom are more difficult to interpret than skin tests for inhaled allergens. Alternatively, serum bee-specific and wasp-specific IgE can be measured by a radioallergosorbent test (RAST), CAP-RAST, or other assays.

    It is important to be aware that since the introduction of the more sensitive CAP-RAST, there have been more (up to 30%) false positive results—that is, patients with serum IgE to both bee and wasp venom (double positives) when they are allergic to only one venom. However, double positives can occur even with the radioallergosorbent test (in about 6% of cases). The term allergy refers to a state of clinical reactivity and is not the same as sensitisation (presence of specific IgE antibodies), which can occur without clinical reactivity. Patients are rarely allergic to both bee and wasp venom. This means that if the history is not checked, and venom IgE to only a single venom is measured, the wrong diagnosis can result. Studies in the general population show that some subjects who have a history of stings but no reactions have venom-specific IgE.

    Drugs used in acute management of reactions to stings

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    Acute management

    Local reactions

    Acute management should be with oral antihistamines, which may be required for several days. A quick acting drug should be used (for example, one of the newer, non-sedative antihistamines). Very large swellings may require intramuscular antihistamines and steroids. Prevention is more effective, and the patient should take a large dose of an antihistamine (double the standard dose) immediately after being stung, before the localised reaction is established, to abrogate incipient angio-oedema.

    Generalised allergic reactions

    Management depends on the severity and the particular features of the reaction, as for any systemic allergic reaction. Cutaneous reactions require oral antihistamines or injected chlorpheniramine. Moderate reactions often require intramuscular chlorpheniramine and hydrocortisone, and treatment for asthma—for example, inhaled ß2 agonists—may be necessary. Severe reactions, including those with marked respiratory difficulty or hypotension, should be treated with adrenaline (intramuscular) followed by chlorpheniramine and hydrocortisone. Other measures, including intravenous fluids, may also be required, but, provided that treatment is started soon after the onset of the reaction, the drugs above are usually all that are needed.

    Adrenaline (intramuscular) is the key drug for severe reactions

    Further management

    After a generalised reaction, patients need further advice and ideally should be referred to an allergy clinic specialising in venom allergy. As there are not many of these in Britain, general practitioners should be aware that there are two options for further management: patients can either be desensitised or be given the appropriate drugs to treat a reaction themselves. To choose the appropriate management, it helps to classify general reactions by severity.

    Classification of systemic allergic reactions to bee or wasp stings

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    Who should be desensitised?

    Desensitisation (immunotherapy)

    Among patients with generalised reactions, those with severe reactions usually require desensitisation, those with mild reactions do not, and those with moderate reactions may or may not. Other factors—such as the risk of a future sting, the interval from the last sting, other medical problems, the ability of the patient to treat himself or herself, and access to medical help—may influence the decision.

    Indications for venom immunotherapy

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    Before desensitisation is given the nature of the sting must be accurately diagnosed and venom-specific IgE demonstrated.

    The indications in Britain for desensitisation are conservative (in some countries any patient with a generalised reaction, no matter how trivial, would be desensitised). This is because, although immunotherapy for hymenoptera venom is highly effective, the high incidence of spontaneous improvement, as well as the side effects of treatment, has to be taken into account. Venom immunotherapy carries a risk (of about 10%) of inducing systemic allergic reactions and can produce anaphylaxis. It should therefore be performed only in specialist centres treating an adequate number of patients each year.

    Self medication for future reactions

    Those not being desensitised should be given oral antihistamines to take if they are stung again. They should take the antihistamines as soon as they are stung to modify or abort reactions. In a patient with a mild generalised reaction this is normally sufficient. Those with moderate or severe reactions should also be given syringes preloaded with adrenaline. They administer a dose of 0.3 mg (0.3 ml of 1/1000 strength) intramuscularly for adults and children from age 5 years. A syringe containing a smaller dose (0.15 mg) suitable for younger children is available, but children with venom allergy rarely need this. If other drugs are required these should be given by doctors or paramedics. All patients should seek the assistance of an adult as soon as they are stung, in case medical help is required.

    Syringes preloaded with adrenaline (for example, EpiPen or Anapen (which is available on a named patient basis)) are available by using the standard prescription form

    Value of self medication

    • The main advantage of self medication is that reactions are treated only if they occur

    • This is sensible because most patients (except beekeepers) are not stung again for years, and the next sting may cause no reaction or a less severe one

    • The disadvantage is that one cannot be certain that the appropriate drugs (especially adrenaline) will be given (early treatment of anaphylaxis is highly effective)

    • The decision on self medication should be reached on an individual basis after balancing all factors and bearing in mind that desensitisation is not without risk

    What does immunotherapy involve?

    Various regimens are available. Conventional immunotherapy, the standard one, entails an initial course of weekly injections over three months, starting with low doses of venom and reaching the highest dose of 100 μg (equivalent to two stings). Thereafter, maintenance injections of the same dose are given at monthly or longer intervals for three years. The treatment can be given only in specialist centres, where resuscitation facilities exist, to conform with the guidelines of the Committee on the Safety of Medicines (1986 and 1994), because of the risk of side effects. Drugs to treat anaphylaxis must be immediately available, and patients have to be kept under observation for one hour after each injection.

    Immunotherapy is expensive and time consuming

    Mechanism of immunotherapy

    T cells secrete cytokines which orchestrate the immune response. T helper (Th) cells are subdivided into Th1 and Th2 subsets, on the basis of their cytokine secreting profile in response to stimulation with antigen or allergen.

    Can we predict the outcome of a future sting?

    • There is no blood test that will reliably predict how a patient will react to a future sting

    • No direct correlation exists between the concentration of venom-specific IgG in the serum and protection from the next sting • There may be no reaction to a sting in spite of the presence of venom IgE

    • Venom IgE will eventually disappear, but this can take many years. Once it has disappeared completely—both from the serum and from the mast cells—a sting cannot produce a reaction

    • Provocation tests are done either with a real sting or with a subcutaneous injection of pure venom. These are the only tests that will reliably show a patient's reactivity, but, although they are very useful, they are not very practicable. Their use is restricted to specialist centres, and they are useful in research

    It has been shown that venom immunotherapy leads to marked changes in cytokine secretion patterns, with a switch from the abnormal Th2 cytokine response to a Th1 response. This may be due to downregulation of the Th2 response (anergy) or immune deviation in favour of a Th1 response, or to both these. The Th2 subset of Th cells produces interleukin 4, interleukin 5, and interleukin 3, which are proallergic, leading to IgE synthesis (interleukin 4) and activating or attracting eosinophils (interleukin 5) and mast cells (interleukin 3). Venom immunotherapy leads to loss of secretion of Th2 cytokines in response to venom stimulation, and, instead, Th1 cytokine production (interleukin 2 and interferon gamma) is induced. Interferon gamma opposes the effect of interleukin 4 in inducing B cells to secrete IgE.

    This cytokine switch will lead in the long term to loss of IgE synthesis and the allergic response but does not explain the fact that, clinically, desensitisation occurs before these changes take place. This suggests that other, earlier operating mechanisms are involved.

    Further reading

    • W Egner, C Ward, Brown DL, Ewan PW. The incidence and clinical significance of specific IgE to both wasp (vespula) and bee (apis) venom in the same patient. Clin Exp Allergy 1998;28:26-34

    • SM McHugh, J Deighton Stewart AG, Lachmann PJ, Ewan PW. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy. Clin Exp Allergy 1995;25:828-38

    • MJ Kampelmacher, van der Zwan JC. Provocation test with a living insect as a diagnostic tool in systemic reactions to bee and wasp venom: a prospective study with emphasis on the clinical aspects. Clin Allergy 1987;17:317-27

    • MD Valentine, KC Schuberth Kagey-Sobotka A, Graft DF, Kwiterovich KA, Szkalo M, et al. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med 1990;323:1601-3

    • AB Kay, ed. Position paper on allergen immunotherapy: report of a British Society for Allergy and Clinical Immunology Working Party. Clin Exp Allergy 1993;23(suppl 3):19-22

    Acknowledgments

    The table on classification of systemic reactions is adapted from Allergy and Allergic Diseases, Kay AB, ed (Insect-sting allergy (Ewan PW)): Blackwell Science, 1997.

    Pamela W Ewan is a Medical Research Council clinical scientist and honorary consultant in allergy and clinical immunology at Addenbrooke's Hospital, Cambridge.

    The ABC of allergies is edited by Stephen Durham, honorary consultant physician in respiratory medicine at the Royal Brompton Hospital, London. It will be published as a book later in the year.