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Hockenhull J, Elremeli M, Cherry MG, et al. A Systematic Review of the Clinical Effectiveness and Cost-Effectiveness of Pharmalgen® for the Treatment of Bee and Wasp Venom Allergy. Southampton (UK): NIHR Journals Library; 2012 Mar. (Health Technology Assessment, No. 16.12.)
A Systematic Review of the Clinical Effectiveness and Cost-Effectiveness of Pharmalgen® for the Treatment of Bee and Wasp Venom Allergy.
Show detailsClarification of research question and scope
Pharmalgen® products (ALK Abelló) are used for the diagnosis and treatment of immunoglobulin E (IgE)-mediated allergy to bee and wasp venom. The aim of this systematic review was to assess whether use of Pharmalgen products is of clinical value when providing VIT to individuals with a history of severe reaction to bee and wasp venom, and whether it would be considered cost-effective compared with alternative treatment options available in the NHS in England and Wales.
Description of health problem
Aetiology, pathology and prognosis
Apidae (bees), Vespidae (wasps and hornets) and Formicidiae (ants) form part of the order Hymenoptera. Bees and wasps have a modified ovipositor at the terminal end of their abdomen that gives them the ability to sting other organisms. Bees possess a barbed stinger, which, together with their venom sac, remains in their victim's skin after they sting. This means that bees are able to sting only once, and die soon afterwards. Wasps' stingers are not barbed and they are therefore capable of delivering more than one venom-injecting sting in their lifetime. Bee and wasp stings contain allergenic proteins. In wasps, these are predominantly phospholipase A1,1 hyaluronidase1 and antigen 52 and, in bees, phospholipase A2 and hyaluronidase.3 It has been estimated that each bee sting contains 147 μg of venom and each wasp sting contains 17 μg of venom.4
The symptoms produced following a sting can be classified into non-allergic and allergic reactions. All envenomated individuals are likely to experience local burning and pain followed by erythema (redness) and a small area of oedema (swelling) at the site of the sting. These are caused by vasoactive components of venom and the mechanism is toxic rather than allergic.4
Following an initial sting, some individuals generate an immune response, which produces antibodies of the IgE class. These antibodies sensitise cells, particularly histamine-containing mast cells, so that allergen re-introduced by a subsequent exposure can bind to the preformed IgE molecules, triggering the cells to produce a rapid inflammatory response (this is referred to as a ‘type 1’ or ‘immediate-type’ hypersensitivity reaction). These allergic reactions in venom-sensitised individuals can be local or systemic, can vary in severity and are typically of rapid onset.5–8 The term ‘anaphylaxis’ is applied to the most severe reactions. These frequently occur within 15 minutes of a sting; initial symptoms are usually cutaneous (flushing, urticaria, angioedema) followed by hypotension (with light-headedness, fainting or collapse) and/or respiratory symptoms (due to an asthma-like response or laryngeal oedema). Progression to fatal cardiorespiratory arrest can occur within several minutes.5 Anaphylaxis occurs more commonly in males and in people under 20 years of age,6 and the species that cause the most frequent allergic reactions in humans following a sting are the Apidae (bees) and the Vespidae (wasps and hornets).7
In addition to local and systemic allergic reactions, individuals may also experience allergic reactions due to circulating immune complexes or delayed hypersensitivity reaction. This is uncommon, and presents as skin rashes and sickness-like symptoms occurring within 3 days to 2 weeks post sting.5
Severity of systemic reactions to Hymenoptera venom can be measured using the Mueller grading system,8 which is summarised in Table 1. The grading system classifies the reaction to a sting according to the severity of symptoms. Severity ranges from grade 1 (symptoms of skin and mucous membranes) to grade 4 (cardiovascular symptoms).
TABLE 1
Mueller grading system.
Epidemiology
In the UK, insect stings are the second most frequent cause of anaphylaxis outside of medical settings,9 and Hymenoptera venoms are one of the three main causes of fatal anaphylaxis in both the USA and the UK.10 It is estimated that the prevalence of bee and wasp sting allergy is between 0.4% and 3.3%.11
The prevalence rates of large local reactions (LLRs) in the general population have been estimated at between 2.4% and 26.4%, and up to 38% in beekeepers.10 Children are reported to have lower rates of both large local and systemic reactions to Hymenoptera stings, at between 11.5% and 19% and between 0.15% and 0.8%, respectively.5 After a LLR, 5–15% of people will go on to develop a systemic reaction when next stung.12
The prevalence of systemic reactions to Hymenoptera venom is not reliably known, but estimates range from 0.5% to 3.3% in the USA,12,13 and from 0.3% to 7.5% in Europe.10 Differences in rates of systemic allergic reactions in children and adults have been reported: up to 3% of adults and almost 1% of children have a medical history of severe sting reactions.11,13 In people with a mild systemic reaction, the risk of subsequent systemic reactions is thought to be between 14% and 20%.12 Within the USA, severe life-threatening reactions occur in 0.4–0.8% of children and 3% of adults.14
UK data
Between two and nine people in the UK die each year as a result of anaphylaxis due to having experienced reactions to bee and wasp stings.15 Once an individual has experienced an anaphylactic reaction, the risk of having a recurrent episode has been estimated to be between 60% and 79%.12 In 2000, the register of fatal anaphylactic reactions in the UK from 1992 to 2000 was reported by Pumphrey and Roberts.16 Of the 56 postmortems carried out during this period, 19 deaths (33.9%) were recorded as reactions to Hymenoptera venom. A retrospective study in 200417 examined all deaths from anaphylaxis in the UK between 1992 and 2001 and estimated 47/212 (22.2%) to have resulted from reactions to Hymenoptera venom during this period.
This further breaks down into 29/47 (61.7%) from reactions to wasp stings and 4/47 (8.5%) from reactions to bee stings, the remaining 14/47 being caused by unidentified Hymenoptera stings (29.8%).17
Current diagnostic options
Currently, individuals can be tested to determine if they are at risk of systemic reactions to bee and wasp venom. The primary diagnostic method for allergic sensitisation to bee and/or wasp stings is venom skin testing.
Venom skin testing involves skin prick testing (SPT) and/or intradermal skin testing (IDT) by injection with Hymenoptera venom protein extracts at concentrations in the range of 0.001–1.0 μg/ml. This establishes the minimum concentration giving a positive result. Guidelines produced by the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the European Academy of Allergy and Clinical Immunology (EAACI)12,18,19 recommend that SPT be the first line of investigation to diagnose Hymenoptera venom allergy, and be performed 2 weeks after the sting reaction. IDT should be used when the results of SPT are negative, as IDT is 90% more sensitive than SPT at a concentration of 1 μg/ml.12 As venom tests show unexplained variability over time,20 and as negative skin tests can occur following recent anaphylaxis, if an individual displays a history of systemic reactions but his or her skin tests are negative it is recommended that tests should be repeated 1–2 months later, along with serum-specific IgE measurement.12
Another method of diagnosis is direct measurement of allergen-specific IgE antibodies in serum (previously, and sometimes still, referred to as radioallergosorbent testing, or RAST, although this is now an anachronistic misnomer). This test is less sensitive than a skin test but is useful when skin tests cannot be carried out, for example in people with skin conditions.21,22
Current treatment options
For treatment of symptoms in the event of being stung, people can be provided with an emergency kit.23 The contents can be tailored to the perceived risk of a severe reaction but the options include an H1-blocking high-dose antihistamine (HDA), a corticosteroid, a bronchodilator and an adrenaline auto-injector (AAI).
Injected adrenaline (a sympathomimetic drug that acts on both alpha- and beta-adrenoceptors), administered as part of hospital treatment, is regarded as the emergency treatment of choice for cases of acute anaphylaxis as a result of Hymenoptera stings.24 For adults, the recommended dose is between 0.3 mg and 0.5 mg via intramuscular injection, and 0.01 mg/kg via intramuscular injection for children. AAIs available in the UK for carriage by individuals at risk of anaphylactic reactions, and designed for immediate self-administration, include EpiPen® (Mylan Inc.) and Anapen® (Lincoln Medical Ltd). These AAIs must be prescribed by a clinician. People and their relatives/carers receive training in using the AAI, and are advised to practise regularly using a suitable training device.25
In addition to emergency treatments, preventative measures include education (avoidance advice) on how to avoid bee and/or wasp stings. Additionally, education includes advice on recognising the early symptoms of anaphylaxis so that individuals summon help quickly and are prepared to use their emergency medication. All those at high risk should consider wearing a device such as a bracelet (e.g. MedicAlert) that provides information about their history of anaphylactic reaction to bee and/or wasp venom.25
Venom immunotherapy
In addition to the measures detailed above, people with a history of a systemic allergic reaction to Hymenoptera venom can be considered for specific allergen immunotherapy. It is recommended that venom immunotherapy (VIT) is considered ‘when positive test results for specific IgE antibodies correlate with suspected triggers and patient exposure’.26 VIT is intended to prevent or reduce the severity of future systemic allergic reactions and can be administered using a variety of products and according to a variety of protocols. Currently, the only products licensed for use in the UK are Pharmalgen products (Table 2).
TABLE 2
Venom immunotherapy products.
Venom immunotherapy consists of subcutaneous injections of increasing amounts of venom, and treatment is divided into two periods: the updosing phase and the maintenance phase. VIT is normally discontinued after 3–5 years, but adjustments to the treatment regime may be necessary when treating people with intense allergen exposure (such as beekeepers) or those with individual risk factors for severe reactions. There are 44 centres across the UK that provide PhVIT to people for bee and wasp sting allergy.27 From the findings of the latest UK audit,14 it is clear that there is no single standard approach to the delivery of PhVIT; different centres appear to follow different dosing and administration protocols and every treatment package is tailored to the requirements of the individual patient.
In 1978, the first randomised controlled trial (RCT)28 assessing the effectiveness of VIT in the treatment of insect venom allergy was published, in which people were randomised to either VIT or placebo. Systemic reactions following re-sting occurred in 7 of 12 people receiving placebo and in 1 of 18 people receiving VIT. As a direct result of this study, it is now considered unethical to randomise people eligible for VIT to receive placebo treatment.
Assessing the effectiveness of venom immunotherapy
The impact of VIT can be assessed using both clinical and psychological outcomes. Clinical outcomes relate to the effectiveness of VIT in reducing the rate of reaction to subsequent stings and the psychological outcomes relate to quality of life (QoL) and anxiety related to fear of future stings.
The effectiveness of VIT has been assessed using various methods. A method frequently used in clinical trials is that of a hospital sting challenge (SC), in which a patient is purposely stung, in a controlled environment, by a living insect of the species to which they have been desensitised. Any reaction to the sting is then reported and treated if necessary. Another measure of effectiveness is that of patient-reported reactions to accidental field stings (FSs). Other methods include the measurement of serum IgE and skin tests similar to those used in the diagnosis of venom allergy. However, there is no completely reliable method of predicting which people will be at risk of further anaphylactic reactions and which will remain anaphylaxis free in the long term, following VIT.26
Local or systemic adverse reactions (ARs) may occur as a result of VIT. They normally develop within 30 minutes of the injection, but occasionally delayed reactions can occur after several hours. Each patient is monitored closely following each injection to check for ARs. These reactions inform the rate of progression to increased doses during the updosing phase of treatment.
Relevant national guidelines
Emergency treatment
The Resuscitation Council of the UK updated guidelines for the emergency treatment of anaphylactic reactions in 2008.25 These guidelines detail the diagnosis, treatment, investigation and follow-up of people who have had an anaphylactic reaction, including those reacting to Hymenoptera venom. Emergency treatment with 0.5 mg of intramuscular adrenaline is recommended for people experiencing an anaphylactic reaction. Intravenous adrenaline is recommended only for occasional use by experienced specialists; subcutaneous or inhaled adrenaline is not recommended. Treatment with the highest concentration of oxygen available via a mask, and loading with 500–1000 ml of fluids (for adults) is also recommended, in addition to adrenaline.
High-dose antihistamines are recommended as a second-line treatment for anaphylaxis to help counter histamine-mediated vasodilatation and bronchoconstriction.25 For adults, chlorphenamine 10 mg intramuscularly or intravenously is recommended. People experiencing an anaphylactic reaction should be treated and then observed for at least 6 hours in a clinical area with facilities for treating life-threatening breathing complications.
The Resuscitation Council of the UK25 also recommends that all people presenting with anaphylaxis should be referred to an allergy clinic to determine the cause of the reaction and to prepare the patient to be able to manage future episodes themselves.
Preventative measures
The AAAAI guidelines for the management and prevention of stinging insect hypersensitivity were first produced in 1999,29 and were subsequently updated in 200430 and 2011.18 They recommend that people who have experienced a systemic reaction to an insect sting should be referred to an allergist–immunologist for skin testing or in vitro testing for venom-specific IgE antibodies. A positive IDT response to insect venom at a concentration of ≤ 1.0 μg/ml demonstrates the presence of specific IgE antibodies, and VIT is recommended. If people have a negative skin test despite a history of anaphylaxis, in vitro testing for IgE antibodies or repeat skin testing is recommended before concluding that VIT is not indicated.
Venom immunotherapy in adults is usually recommended for all individuals who have experienced systemic reactions, but is generally not necessary for individuals who have had only an LLR because of low risk of a systemic reaction to a subsequent sting. The AAAAI18 recommends that, once started, VIT should be continued for at least 3–5 years. During this time, and in people who did not commence VIT, it is recommended that people carry an AAI at all times.
The technology
Pharmalgen products are produced by ALK Abelló and have had UK marketing authorisation for the diagnosis (using skin testing/intracutaneous testing) and treatment (using PhVIT) of IgE-mediated allergy to bee venom (Pharmalgen Bee Venom) and wasp venom (Pharmalgen Wasp Venom) since March 1995 (marketing authorisation number PL 10085/0004).31 The active ingredient is freeze-dried Apis mellifera venom in Pharmalgen bee venom and partially purified, freeze-dried Vespula spp. venom in Pharmalgen wasp venom, each provided with a solvent to prepare for injection.
Before treatment is considered, allergy to bee or wasp venom must be confirmed by case history and diagnostic testing as outlined previously. Treatment with Pharmalgen bee or wasp venom is performed by subcutaneous injection. The treatment is carried out in two phases: the updosing phase and the maintenance phase.
In the updosing phase, the dose is increased stepwise until the maintenance dose (the maximum tolerable dose before an allergic reaction, or a maximum dose of 100 μg, whichever is the smaller) is achieved. ALK Abelló recommends the following dosage protocols: ‘conventional’, ‘modified rush’ (clustered) and ‘rush’ updosing. In conventional updosing, the patient receives one injection every 3–7 days. In modified rush (clustered) updosing, the patient receives two to four injections once a week. If necessary, this interval may be extended up to 2 weeks. The two to four injections are given with an interval of 30 minutes. In rush updosing, while hospitalised, the patient receives injections at 2-hour intervals and a maximum of four injections per day may be given in the updosing phase. An ultra-rush protocol has also been used in some studies in which hospitalised patients receive all injections in one day at 30-minute intervals.32
The updosing phase ends when the individual maintenance dose has been attained and the interval between the injections is increased by 2, 3 or 4 weeks. This is called the maintenance phase, and the maintenance dose is then given every 4–6 weeks for at least 3 years.
In the UK, treatment is carried out in hospital, either as an outpatient for conventional updosing or as an inpatient for rush protocols. Treatment is administered by a specialist, and emergency resuscitation equipment should be available in case it is required to treat any systemic reaction. Venom from ALK Abelló is used in most clinics in the UK, with 92% of clinics employing the conventional 12-week updosing protocol and the remainder employing a clustered (7- to 8-week) updosing protocol.14
For bee venom-sensitised people, the relevant PhVIT preparation costs £54.81 during the updosing phase and then £15.94 per injection during the maintenance phase. For wasp venomsensitised people, PhVIT costs £67.20 during the updosing phase and then £20.51 per injection during the maintenance phase.
Contraindications/warnings
The Pharmalgen summary of product characteristics (SmPC)31 lists several contraindications to PhVIT treatment. These are immunological diseases (e.g. immune complex diseases and immune deficiencies), chronic heart/lung diseases, treatment with beta-blockers and severe eczema. Side effects include superficial wheal and flare, local swelling (which may be immediate or delayed up to 48 hours), mild general reactions (urticaria, erythema, rhinitis or mild asthma) and moderate or severe general reactions (more severe asthma, angioedema or anaphylactic reaction with hypotension and respiratory embarrassment and possible death).31
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