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1、The clinical and cost-effectiveness of Pharmalgen for the treatment of bee and wasp venom allergy 1 TITLE OF PROJECT The clinical and cost effectiveness of Pharmalgen for the treatment of bee and wasp venom allergy 2 TAR TEAM Liverpool Reviews and Implementation Group (LRiG), University of Liverpool

2、 Correspondence to: Rumona Dickson, Ms Director, LRiG University of Liverpool Room 2.12 Whelan Building The Quadrangle Brownlow Hill Liverpool L69 3GB Tel: +44 (0) 151 794 5682 Fax: +44 (0)151 794 5585 Email For details of expertise within the TAR team, see section 7. 3 PLAIN ENGLISH SUMMARY Allergi

3、c reactions to bee and wasp venom may occur in venom-sensitive patients immediately following a sting, and can vary in severity, with initially mild symptoms sometimes progressing to critical conditions within seconds. The most severe systemic allergic reactions (generalised reactions) are known as

4、anaphylaxis, a reaction characterised by abnormally low blood pressure, fainting or collapse, and in extreme reactions these symptoms can cause death. Each year in the UK there are between two and nine deaths from anaphylaxis caused by bee and wasp venom. The immediate treatment for severe allergic

5、reactions to bee and wasp venom consists of emergency treatment with drugs to decrease the patients response to the venom and support breathing, if required. To avoid further reactions, the use of sensitisation to bee and wasp venom, through a process known as venom immunotherapy (VIT), has been inv

6、estigated. Venom immunotherapy consists of subcutaneous injections of increasing amounts of venom into patients with a history of anaphylaxis to bee and wasp venom. Pharmalgen has had UK marketing authorisation for the diagnosis and treatment (using VIT) of allergy to bee venom (using Pharmalgen Bee

7、 Venom) and wasp venom (using Pharmalgen Wasp Venom) since March 1995, and it is used by more than 40 centres across the UK. This review aims to assess whether using Pharmalgen in VIT is clinically useful when treating people with a history of severe reaction to bee and wasp stings. The review will

8、compare preventative treatment with Pharmalgen to other treatment options, including high dose antihistamines, advice on the avoidance of bee and wasp stings and adrenaline auto-injector prescription and training. If suitable data are available, the review will also consider the cost effectiveness o

9、f using Pharmalgen for VIT and other subgroups including children and people at high risk of future stings or severe allergic reactions to future stings. 4 DECISION PROBLEM 4.1 Clarification of research question and scope Pharmalgen is used for the diagnosis and treatment of immunoglobin E (IgE)-med

10、iated allergy to bee and wasp venom. The aim of this report is to assess whether the use of Pharmalgen is of clinical value when providing VIT to individuals with a history of severe reaction to bee and wasp venom and whether doing so would be considered cost effective compared with alternative trea

11、tment options available in the NHS. 4.2 Background Bees and wasps form part of the order Hymenoptera (which also includes ants), and within this order the species that cause the most frequent allergic reactions are the Vespidae (wasps, yellow jackets and hornets), and the Apinae (honeybees).1 Bee an

12、d wasp stings contain allergenic proteins. In wasps, these are predominantly phospholipase A1,2 hyaluronidase2 and antigen 5,3 and in bees are phospholipase A2 and hyaluronidase.4 Following an initial sting, a type 1 hypersensitivity reaction may occur in some individuals which produces the IgE anti

13、body. This sensitises cells to the allergen, and any subsequent exposure to the allergen may cause the allergen to bind to the IgE molecules, which results in an allergic reaction. These allergens typically produce an intense, burning pain followed by erythema (redness) and a small area of oedema (s

14、welling) at the site of the sting. The symptoms produced following a sting can be classified into non-allergic reactions, such as local reactions, and allergic reactions, such as extensive local reactions, anaphylactic systemic reactions and delayed systemic reactions.5-6 Systemic allergic reactions

15、 may occur in venom-sensitive patients immediately following a sting,7 and can vary in severity, with initially mild symptoms sometimes progressing to critical conditions within seconds.1 The most severe systemic allergic reaction is known as anaphylaxis. Anaphylactic reactions are of rapid onset (t

16、ypically up to 15 minutes post sting) and can manifest in different ways. Initial symptoms are usually cutaneous followed by hypotension, with light-headedness, fainting or collapse. Some people develop respiratory symptoms due to an asthma-like response or laryngeal oedema. In severe reactions, hyp

17、otension, circulatory disturbances, and breathing difficulty can progress to fatal cardio-respiratory arrest. Anaphylaxis occurs more commonly in males and in people under 20 years of age and can be severe and potentially fatal.8 4.3 Epidemiology It is estimated that the prevalence of wasp and bee s

18、ting allergy is between 0.4% and 3.3%.9 The incidence of systemic reactions to wasp and bee venom is not reliably known, but estimates range from 0.15-3.3%,10-11 Systemic allergic reactions are reported by up to 3% of adults, and almost 1% of children have a medical history of severe sting reactions

19、.9, 12 After a large local reaction, 515% of people will go on to develop a systemic reaction when next stung.13 In people with a mild systemic reaction, the risk of subsequent systemic reactions is thought to be about 18%.13 Hymenoptera venom are one of the three main causes of fatal anaphylaxis in

20、 the USA and UK.14-15 Insect stings are the second most frequent cause of anaphylaxis outside of medical settings.16 Between two and nine people in the UK die each year as a result of anaphylaxis due to reactions to wasp and bee stings.17 Once an individual has experienced an anaphylactic reaction,

21、the risk of having a recurrent episode has been estimated to be between 60% and 79%.13 In , the register of fatal anaphylactic reactions in the UK from 1992 onwards was reported by Pumphrey to determine the frequency at which classic manifestations of fatal anaphylaxis are present.18 Of the 56 post-

22、mortems carried out, 19 deaths were recorded as reactions to Hymenoptera venom (33.9%). A retrospective study in examined all deaths from anaphylaxis in the UK between 1992 and , and estimated 22.19% to be reactions to Hymenoptera venom (47/212). This further breaks down into 29/212 (13.68%) as reac

23、tions to wasp stings, and 4/212 (1.89%) as reactions to bee stings. The remaining 14/212 were unidentified Hymenoptera stings (6.62%).19 4.4 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 diagn

24、ostic method for systemic reactions to bee and/or wasp stings is venom skin testing. Skin testing involves intradermal injection with the five Hymenoptera venom protein extracts, with venom concentrations in the range of 0.001 to 1.0 g/ml. This establishes the minimum concentration giving a positive

25、 result (a reaction occurring in the individual). As venom tests show unexplained variability over time,20 and as negative skin tests can occur following recent anaphylaxis, it is recommended that tests be repeated after 1 to 6 months.21 Other methods of diagnosis in patients following an anaphylact

26、ic reaction include radioallergosorbent test (RAST), which detects allergen-specific IgE antibodies in serum. This test is less sensitive than skin testing but is useful when skin tests cannot be done, for example in patients with skin conditions.22-23 4.5 Current treatment options Preventative trea

27、tments include education on how to avoid bee and wasp venom, and prescription of high dose antihistamines. Patients with a history of moderate local reactions should be provided with an emergency kit,24 containing a H1-blocking antihistamine and a topical corticosteroid for immediate use following a

28、 sting. Patients with a history of anaphylaxis should be provided with an emergency kit containing a rapid-acting H1-blocking antihistamine, an oral corticosteroid and an auto-injector for self administration, containing epinephrine. Injected epinephrine (a sympathomimetic drug which acts on both al

29、pha and beta receptors) is regarded as the emergency treatment of choice for cases of acute anaphylaxis as a result of Hymenoptera stings.25 For adults, the recommended dose is between 0.30 mg/ml and 0.50 mg/ml I.M, and 0.01 ml/kg I.M. for children. Individuals with a history of anaphylactic reactio

30、ns are recommended to carry auto injectors containing epinephrine (commonly known as EpiPen, Adrenaclick, Anapen or Twinject). These are intended for immediate self-administration by individuals with a history of hypersensitivity to Hymenoptera stings and other allergens. Preventive measures followi

31、ng successful treatment of a systemic allergic reaction to Hymenoptera venom consists of either allergen avoidance or specific allergen immunotherapy, known as VIT. Venom immunotherapy is considered to be a safe and effective treatment.26 Currently, VIT can be used with several regimes, including Ph

32、armalgen (manufactured by ALK Abello, and licensed in the UK), Aquagen and Alutard SQ (both manufactured by ALK Abello and unlicensed in the UK but licensed in some parts of Europe), VENOMENHAL (HAL Allergy, Leiden, Netherlands, unlicensed in the UK), Alyostal (Stallergenes, Antony Cedex, France, un

33、licensed in the UK), and Venomil (Hollister-Stier Laboratories LLC, unlicensed in the UK). Venom immunotherapy is recommended to prevent future systemic reactions. It is recommended that VIT is considered when positive test results for specific IgE antibodies correlate with suspected triggers and pa

34、tient exposure.27 Venom immunotherapy consists of subcutaneous injections of increasing amounts of venom, and treatment is divided into two periods: the build up phase and maintenance phase. Venom immunotherapy is now the standard therapy for Hymenoptera sting allergy,28 and is a model for allergen-

35、specific therapy,29-30 with success rates (patients who will remain anaphylaxis free) being reported as more than 98% in some studies.4, 31 There are now 44 centres across the UK which provide VIT to people for bee and wasp sting allergy. Venom immunotherapy is normally discontinued after 3 to 5 yea

36、rs, but modifications may be necessary when treating people with intense allergen exposure (such as beekeepers) or those with individual risk factors for severe reactions. There is no method of assessing which patients will be at risk of further anaphylactic reactions following administration of VIT

37、 and those who will remain anaphylaxis free in the long term following VIT.27 Local or systemic adverse reactions may occur as a result of VIT. They normally develop within 30 minutes of the injection. Each patient is monitored closely following each injection to check for adverse reactions. Progres

38、sion to an increased dose only occurs if the previous dose is fully tolerated. 4.6 The technology Pharmalgen is produced by ALK Abello, and has had UK marketing authorisation for the diagnosis (using skin testing/intracutaneous testing) and treatment (using VIT) of IgE-mediated allergy to bee venom

39、(Pharmalgen Bee Venom) and wasp venom (Pharmalgen Wasp Venom) since March 1995 (marketing authorisation number PL 10085/0004). The active ingredient is partially purified freeze dried Vespula spp. venom in Pharmalgen Wasp Venom and freeze dried Apis mellifera venom in Pharmalgen Bee Venom, each prov

40、ided in powder form for solution for injection.Before treatment is considered, allergy to bee or wasp venom must be confirmed by case history and diagnosis. Treatment with Pharmalgen Bee or Wasp Venom is performed by subcutaneous injections. The treatment is carried out in two phases: the initial ph

41、ase and the maintenance phase. In the build up phase, the dose is increased stepwise until the maintenance dose (the maximum tolerable dose before an allergic reaction) is achieved. ALK Abello recommends the following dosage proposals: conventional, modified rush (clustered) and rush updosing. In co

42、nventional updosing, the patient receives one injection every 3-7 days. In modified rush (clustered) updosing, the patient receives 2-4 injections once a week. If necessary this interval may be extended up to two weeks. The 2-4 injections are given with an interval of 30 minutes. In rush updosing, w

43、hile being hospitalised the patient receives injections with a 2-hour interval. A maximum of four injections per day may be given in the initial phase. The build up phase ends when the individual maintenance dose has been attained and the interval between the injections is increased to 2, 3 and 4 we

44、eks. This is called the maintenance phase, and the maintenance dose is then given every 4 weeks for at least 3 years. Contra-indications to VIT treatment are immunological diseases (e. g. immune complex diseases and immune deficiencies); chronic heart/lung diseases; treatment with -blockers; severe

45、eczema. Side effects include superficial wheal and flare due to shallow injection; local swelling (which may be immediate or delayed up to 48 hours); mild general reactions such as urticaria, erythema, rhinitis or mild asthma; moderate or severe general reactions such as more severe asthma, angioede

46、ma or an anaphylactic reaction with hypotension and respiratory embarrassment; anaphylaxis (often starting with erythema and pruritus, followed by urticaria, angioedema, nasal or pharyngial congestion, wheezing, dyspnoea, nausea, hypotension, syncope, tachycardia or diarrhoea). 32 4.7 Objectives of

47、the HTA project The aim of this review is to assess the clinical and cost effectiveness of Pharmalgen in providing immunotherapy to individuals with a history of type 1 IgE-mediated systemic allergic reaction to bee and wasp venom. The review will consider the effectiveness of Pharmalgen when compar

48、ed to alternative treatment options available in the NHS, including advice on the avoidance of bee and wasp stings, high dose antihistamines and adrenaline auto-injector prescription and training. The review will also examine the existing health economic evidence and identify the key economic issues

49、 related to the use of Pharmalgen in UK clinical practice. If suitable data are available, an economic model will be developed and populated to evaluate if the use of Pharmalgen for the treatment of bee and wasp venom allergy, within its licensed indication, would be a cost effective use of NHS reso

50、urces. 5 METHODS FOR SYNTHESISING CLINICAL EFFECTIVENESS EVIDENCE 5.1 Search strategy The major electronic databases including Medline, Embase and The Cochrane Library will be searched for relevant published literature. Information on studies in progress, unpublished research or research reported in

51、 the grey literature will be sought by searching a range of relevant databases including National Research Register and Controlled Clinical Trials. A sample of the search strategy to be used for MEDLINE is presented in Appendix 1. Bibliographies of previous systematic reviews, retrieved articles and

52、 the submissions provided by manufacturers will be searched for further studies. A database of published and unpublished literature will be assembled from systematic searches of electronic sources, hand searching, contacting manufacturers and consultation with experts in the field. The database will

53、 be held in the Endnote X4 software package. 5.1.1 Inclusion criteria The inclusion criteria specified in Table 1 will be applied to all studies after screening. The inclusion criteria were selected to reflect the criteria described in the final scope issued by NICE for the review. However, as there

54、 is likely to be a limited amount of RCT data, the inclusion criteria of study design may be expanded to include comparative studies and descriptive cohorts. The clinical and cost effectiveness of Pharmalgen for the treatment of bee and wasp venom allergy Page 11 of 21 Table 1: Inclusion criteria In

55、tervention(s) Pharmalgen for the treatment of bee and wasp venom allergy, Population(s) People with a history of type 1 IgE-mediated systemic allergic reactions to: wasp venom and/or bee venom Comparators Alternative treatment options available in the NHS, without venom immunotherapy including: advi

56、ce on the avoidance of bee and wasp venom, high-dose antihistamines, adrenaline auto-injector prescription and training Study design Randomised controlled trials Systematic reviews Outcomes Outcome measures to be considered include: number and severity of type 1 IgE-mediated systemic allergic reacti

57、ons mortality anxiety related to the possibility of future allergic reactions adverse effects of treatment health-related quality of life Other considerations If the evidence allows, considerations will be given to subgroups of people, according to their: risk of future stings (as determined, for ex

58、ample, by occupational exposure) risk of severe allergic reactions to future stings (as determined by such factors as baseline tryptase levels and co-morbidities) If the evidence allows, the appraisal will consider separately people who have a contraindication to adrenaline. If the evidence allows,

59、the appraisal will consider children separately. Two reviewers will independently screen all titles and abstracts of papers identified in the initial search. Discrepancies will be resolved by consensus and where necessary a third reviewer will be consulted. Studies deemed to be relevant will be obta

60、ined and assessed for inclusion. Where studies do not meet the inclusion criteria they will be excluded.5.1.2 Data extraction strategy Data relating to study design, findings and quality will be extracted by one reviewer and independently checked for accuracy by a second reviewer. Study details will

61、 be extracted using a standardised data extraction form. If time permits, attempts will be made to contact authors for missing data. Data from studies presented in multiple publications will be extracted and reported as a single study with all relevant other publications listed. 5.1.3 Quality assess

62、ment strategy The quality of the clinical-effectiveness studies will be assessed according to criteria based on the CRDs guidance for undertaking reviews in healthcare.33-34 The quality of the individual clinical-effectiveness studies will be assessed by one reviewer, and independently checked for a

63、greement by a second. Disagreements will be resolved through consensus and if necessary a third reviewer will be consulted. 5.1.4 Methods of analysis/synthesis The results of the data extraction and quality assessment for each study will be presented in structured tables and as a narrative summary.

64、The possible effects of study quality on the effectiveness data and review findings will be discussed. All summary statistics will be extracted for each outcome and where possible, data will be pooled using a standard meta-analysis.35 Heterogeneity between the studies will be assessed using the I2 t

65、est.34 Both fixed and random effects results will be presented as forest plots.6 METHODS FOR SYNTHESISING COST EFFECTIVENESS EVIDENCE The economic section of the report will be presented in two parts. The first will include a standard review of relevant published economic evaluations. If appropriate and data are available, the second will include the development of an economic model. The model will be designed to estimate the cost effectiveness of Pharmalgen for VIT in individuals with a history of anaphylaxis to bee and wasp venom. This section of the report