Population
The indication for this assessment is to evaluate the clinical effectiveness and cost-effectiveness of using multiplex allergen testing [ImmunoCAP® Immuno-Solid phase Allergy Chip (ISAC) (Thermo Fisher Scientific/Phadia AB, Uppsala, Sweden) or Microtest (Microtest Matrices Ltd, London, UK)] as an adjunct to current clinical investigations in people with allergy that is difficult to manage (defined as people who are allergic to two or more allergens and/or have allergies to unknown sources).
Multiplex allergen testing is likely to be used in secondary care settings or specialist tertiary care centres, as an addition to allergen challenge testing and in addition to, or in place of, some sIgE antibody testing. Multiplex allergen testing may replace some IgE testing, but where the multiplex testing panel does not include all of the suspected allergens, additional sIgE tests may be needed.
Allergy is a term used to describe immune-mediated hypersensitivity to external stimuli (allergens). Immune-mediated hypersensitivity reactions are divided into two categories: IgE-mediated reactions and non-IgE-mediated reactions. IgE antibodies are normally present in very small amounts in the body, but levels are raised in allergic disease. IgE-mediated immune reactions, also called type 1 hypersensitivity reactions, are typically rapid in onset and can involve extreme acute symptoms as in anaphylaxis or prolonged symptoms (e.g. urticaria or eczema). In an IgE-mediated reaction IgE binds to allergen molecules, which are then taken up by receptors on the surface cells of the immune system, causing the release of biologically active agents and consequent response: vasodilation (widening of blood vessels); increased capillary permeability; mucus hypersecretion; smooth muscle contraction; and tissue inflammation.
Non-IgE-mediated reactions are less well understood and are mediated by other components of the immune system. They are typically delayed in onset, and occur 4–28 hours after exposure.
This assessment will focus on IgE-mediated hypersensitivity.
Sensitisation describes the process at the start of the immune response. Exposure to an allergen [e.g. house dust mite (HDM) or pollen] initiates a complex set of cellular events within the human body, leading to the production of a specific IgE antibody to a specific allergen. At this point there is no clinical reaction (rash, sneezing). Upon re-exposure, the allergen can bind to the specific antibody that orchestrates the immune system to initiate a more aggressive and rapid response, resulting in an inflammatory response with clinical symptoms. However, many ‘sensitised’ individuals do not experience clinical reactions upon subsequent exposure to allergen, a situation known as tolerance.
The term polysensitisation usually refers to sensitisation to two or more allergen sources, and the term paucisensitisation has been used to describe sensitisation to between two and four allergens. Clinical reactivity can be difficult to diagnose in polysensitised patients because of problems distinguishing between sensitisation to cross-reactive allergens. Cross-reactivity occurs when the molecular structure/shape of two different antigens is very similar and the antibody recognises the two different antigens as the same antigen; for example, an IgE antibody that recognises and causes an allergic reaction to Bet v 1 in birch pollen can also trigger an allergic response to Cor a1 in hazelnut. In nature there are many molecules with similar molecular structures/shapes and this translates into the clinic as an obstacle when trying to identify all potential allergens that might cause an allergic reaction in a given patient. Currently, patients undergo allergy testing to identify the allergens to which they are sensitive. This is based on skin prick testing or identifying the presence of individual antibodies in the bloodstream using single IgE tests. For both methods, it is difficult to identify multiple cross-reactive allergens for patients who appear to be polysensitised or have difficult to diagnose allergic disease. It has been claimed that multiplex allergen testing may provide improved information about the sensitisation profile in polysensitised patients. This assessment will summarise the available data on information provided by multiplex allergen testing, which is additional to that obtained from single IgE tests and/or skin prick or allergen challenge tests.
It is difficult to obtain reliable statistics on allergy prevalence in the UK. The charity Allergy UK states, on its website, that there are an estimated 21 million adults in the UK who have at least one allergy and that an estimated 10 million of these have two or more allergies;1 however, these figures appear to be taken from a 2010 report on allergy and allergy remedies from the market research company Mintel. Data from the QRESEARCH project, a database containing the psuedoanonymised health records of over 13 million people, from 950 UK general practices,2 can provide some information on the prevalence of allergy symptoms and diagnoses seen in primary care and on changing patterns over time. At the end of 2005, QRESEARCH data indicated that approximately one in nine people had a recorded diagnosis of ‘any allergic disease’ (including asthma, hay fever, eczema, anaphylaxis or peanut allergy); this figure represented a 27.7% increase over a 4-year period.3 Increases in the incidence of eczema and allergic rhinitis were reported for the same time period; the age- and sex-standardised incidence of eczema was 9.58 per 1000 patient-years in 2001, rising to 13.58 per 1000 patient-years in 2005,4 with the corresponding figures for allergic rhinitis being 5.57 per 1000 patient-years and 7.41 per 1000 patient-years, respectively.5 QRESEARCH data also indicate that the incidence of multiple allergic disorders is increasing. The age- and sex-standardised incidence of multiple allergic disorders was 4.72 per 1000 patient-years in 2001, rising to 6.28 per 1000 patient-years in 2005.6 Alongside data on increasing incidence of allergic disease, QRESEARCH reports also record increases in the number of allergy-related prescriptions and general practice consultations, which are indicative of an increasing burden upon the UK NHS.4–6 There are no QRESEARCH publications that specifically report on food allergy. NICE Clinical Guideline 1167 (food allergy in children and young people) reports an estimated prevalence for self-reported food allergy of between 3% and 35% for individual foods. However, the guideline also notes that only 25–40% of self-reported food allergy is confirmed by oral food challenge (OFC) testing.7
Allergic disease can present as a severe, life-threatening reaction (anaphylaxis). The National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network have recommended that anaphylaxis be defined as ‘a serious allergic reaction that is rapid in onset and may cause death’ and is likely to be the diagnosis when there is involvement of skin or mucosal tissue (e.g. hives, angioedema) and airway compromise (wheezing, dyspnoea) and/or reduced blood pressure or associated symptoms (hypotonia, syncope), along with a temporal relationship (minutes to several hours) to a potential causative agent.8 There are limited data on the incidence of anaphylaxis in the UK. Hospital Episode Statistics record ‘allergy (including anaphylaxis)’ as the primary diagnosis associated with Accident and Emergency attendance for around 70,000 cases (approximately 0.4% of all reports) in both 2013 and 2014; however, no separate statistics are recorded for anaphylaxis.9 A 2010 study,10 based on the Health Improvement Network database, estimated the UK incidence of anaphylaxis at 21.3 [95% confidence interval (CI) 17.6 to 25.4] per 100,000 patient-years. This study included 382 cases of anaphylaxis and the causes were listed as drug (27%); food (24%); insect (12%); latex (0.8%); idiopathic (27%); and no information (10%).10 NICE Clinical Guideline 13411,12 (anaphylaxis assessment) reports an estimate of 20 UK deaths per year from anaphylaxis from a study conducted in 2000. A study published in 2015,13 which analysed data from 1992 to 2012, shows that mortality has not risen, despite an increase in hospitalisations.
Where data are available, this assessment will focus on studies conducted in the people with allergy that is difficult to manage. If data are lacking for this population, studies conducted in patients with specific allergic disease (e.g. peanut allergy) will not be excluded and all potential clinical applications of multiplex allergen testing will be considered.
Intervention technologies
ImmunoCAP Immuno-Solid phase Allergy Chip
The ImmunoCAP ISAC is a miniaturised immunoassay platform (multiple allergen components immobilised on a slide) that is intended to assess the presence of multiple antibodies in a single blood test. IgE antibodies from the patient’s blood sample bind to the immobilised allergen components on the slide, and allergen-bound IgE antibodies are then detected using fluorescence-labelled anti-IgE antibodies. Slides are read using a separate microarray scanner and image analysis software. Using these technologies may provide more detailed information about individual sensitisation profiles than single IgE testing. ImmunoCAP ISAC is intended for use in complex allergy cases, such as those with inconsistent case histories/unsatisfactory response to treatment, those who are polysensitised and patients with idiopathic anaphylaxis. These are people with severe or unclear allergic disease who test positive to a range of allergens but in whom the true cause of symptoms can be difficult to identify. It is claimed that using the ImmunoCAP ISAC test could improve health outcomes by improving allergy management, more appropriately targeting specific immunotherapy, and reducing the number of investigative diagnostic tests. These improvements could also lead to potential savings to the NHS from reducing the number of tests and avoiding the use of unnecessary immunotherapy.
ImmunoCAP ISAC 112 is a molecular diagnostic test that can simultaneously test for IgE antibodies to 112 components from 51 allergen sources. The ISAC is a miniaturised immunoassay platform that uses a single sample (30 μl) of serum, plasma or capillary blood to test for IgE antibodies to multiple allergens. ImmunoCAP ISAC is a two-step assay. IgE antibodies from the patient sample bind to immobilised allergen components spotted in triplets on polymer-coated slides. Each slide contains four microarrays, giving results for four samples per slide. The results are measured using a biochip scanner [confocal laser scanning devices, in particular the CapitalBio LuxScan 10k microarray scanner (Capitalbio, San Diego, CA, USA), are recommended] and evaluated using proprietary software produced by the same company, Phadia Microarray Image Analysis software (MIA) (Phadia AB, Uppsala, Sweden). ImmunoCAP ISAC is a semi-quantitative test and results are reported in International Standard Units (ISUs), giving indications of specific IgE antibody levels; the operating range is 0.3–100 ISU for IgE (ISU-E). This range approximately corresponds to a concentration range of 0.3–100 kilo international units of allergen-specific-antibody per unit volume of sample (kUA/l) of IgE (1 kUA/l is equal to 2.4 ng/ml). The assay takes a total of 4 hours, including sample processing and incubation time.
Microtest
The Microtest Instrument is a CE (Conformité Européenne)-marked automated immunoassay platform that uses microarrays to simultaneously test for 26 allergen components. It is designed for processing and reading protein microarrays of allergens printed in the biochips. The Microtest instrument can simultaneously process up to five Microtest biochips, each containing a different serum sample, in each run. The process is fully automated. When the test is completed, the Microtest Instrument uses a fluorimeter to read the microarrays and the results are semi-quantitative, reported on an allergy risk scale of 0–4. The user can print or export the reports as appropriate. Microtest is intended for use in any patient (infants, children and adults) presenting with allergy symptoms.
summarises the key characteristics of the multiplex allergen tests ImmunoCAP ISAC and Microtest, compared with comparator tests that are currently used in the standard diagnostic work-up of patients with difficult to manage allergic disease.
There are a number of poorly understood factors that influence whether or not clinical symptoms manifest at a certain IgE level, including inhibitory allergen-specific antibodies of non-IgE subclass. Furthermore, other factors, for example age, patient population, concomitant exposure to other allergens, other clinical conditions such as infections, etc., can also affect the degree of symptoms which may occur following allergen exposure. Thus it is not possible to establish general cut-off values valid for all patients at all times. However, when combined with clinical history, the results of multiplex allergen testing may aid the clinician in the diagnosis of allergy. Multiplex allergen testing should always be used in conjunction with allergy-focused clinical history and may be used in addition to, or in place of, single IgE antibody tests and/or skin prick testing.
Comparator
The comparator for this assessment will be current standard care, which should always include allergy-focused clinical history and can additionally involve tests of IgE antibody status (single IgE antibody testing), tests of clinical reactivity such as skin prick testing or allergen challenge testing, or a combination of these approaches.
Single immunoglobulin E testing
Allergen-specific IgE antibody assays are designed to detect and quantify circulating IgE antibodies to one allergen. The choice of which antibodies to test for is based on the clinical history of the patient, and several single IgE tests and/or a stepwise strategy which tests for the most likely causative agents first may be required.
The single IgE test process involves incubation of a blood sample with specific IgE antibodies. Allergen-specific IgE in the patient’s sample binds to the allergen, and unbound antibodies and excess sample are then removed by washing. Anti-IgE antibody, labelled to enable detection (e.g. fluorescently labelled anti-IgE antibody), is then added. The amount of bound allergen-specific IgE is calculated via a standard calibration curve, which is linked to the World Health Organization (WHO) IgE standard and reported in arbitrary mass units (kUA/l).
Higher levels of IgE are considered to be associated with allergy, but the amount of IgE is not predictive of the severity of reaction. Not all patients with a positive specific IgE test will have clinically manifest allergic reaction when exposed to that allergen. Unlike IgE antibody testing, skin prick tests (SPTs) and allergen challenge tests can provide direct information about clinical reactivity to a given allergen.
Skin prick testing
Skin prick testing is a method used to assist in the diagnosis of IgE-mediated allergic disease in patients with rhinoconjunctivitis, asthma, urticaria, anaphylaxis, atopic eczema or gastrointestinal symptoms that are suspected (based on clinical history) to be caused by type 1 (immediate) allergic reaction. It provides evidence for sensitisation in the form of reaction to allergenic stimulus.
The test involves putting a drop of liquid allergen onto the skin, followed by a gentle pin prick through the drop. SPT interpretation utilises the presence and degree of skin reactivity as a marker for sensitisation. When relevant allergens are introduced into the skin, an IgE-mediated immune response occurs. This produces a ‘weal and flare’ response, which can be quantified. Many different allergens can be tested simultaneously because the resultant reaction to a specific allergen is localised to the immediate area of the SPT.
One potential advantage of SPTs compared with in vitro measurement of IgE antibodies is that the test can be interpreted within 15–20 minutes after the reagent is applied to the skin, and therefore results can potentially be given to the patient in the same consultation. SPT results provide evidence of IgE in skin-resident mast cells which may, but does not always, correlate with clinical reactivity. SPTs can also be utilised to test less common allergens, (e.g. medications, and fresh fruits and vegetables) where no specific IgE antibody assays are available. As with any test, the results of SPTs must be interpreted in the context of medical history, clinical symptoms and, where appropriate, other test results. It has been suggested that skin prick testing is an inexpensive option. However, whilst the test materials may be relatively inexpensive, any estimation of costs should consider the staff time needed to perform these tests in an appropriate and safe health-care setting.
Skin prick testing has the following limitations:
Skin reactivity might be affected by previous ingestion of antihistamines or other drugs.
Children may not tolerate multiple skin needle pricks.
Prior or coexisting dermatological conditions, such as eczema, may preclude the performance of skin tests.
The potency of antigen extracts needs to be maintained.
Systemic reactions, although very rare, may occur.
SPTs alone are not sufficient as a confirmatory test.
Allergen challenge testing
Oral food challenges or inhalant challenges are indicated where there is a discrepancy between clinical history and other test results, and can be useful in establishing the identity of specific triggers. The most rigorous method for allergen challenge tests is double blinded and placebo controlled, thus requiring two separate visits. Therefore, single (patient)-blind and open challenges are more frequently performed because only one visit is required. An open challenge describes a challenge in which the patient can recognise the target trigger and there is no attempt at blinding; this is the least time-intensive type of challenge test, but may produce less reliable results as there is the potential for the result to be influenced by either the patient’s anxiety about a particular trigger and/or the health-care professional’s expectations. The general methodology of any challenge test is to administer the trigger in gradually increasing doses in a medical setting. Allergen challenge tests should be performed in a setting that is fully equipped for emergency treatment if an episode of anaphylaxis occurs.
Care pathway
There are a number of National Institute for Health and Care Excellence (NICE) guidelines that consider elements of the diagnosis, management and treatment of allergy.7,11,14,15
Diagnosis
Clinical guidelines consistently emphasise the importance of obtaining a clinical history and asking specific, allergy-focused questions.7,15,16 NICE Clinical Guideline 1167 (food allergy in children and young people) states that this can be done by general practitioners or other primary health-care professionals with the appropriate competencies. According to the guidelines, the following should be included when taking a clinical history:
Any personal history of atopic disease (asthma, eczema or allergic rhinitis).
Any individual and family history of atopic disease (such as asthma, eczema or allergic rhinitis) or food allergy in parents or siblings.
Details of any foods that are avoided and the reasons why.
An assessment of presenting symptoms and other symptoms that may be associated with food allergy, including questions about:
the age of the child or young person when symptoms first started
speed of onset of symptoms following food contact
duration of symptoms
severity of reaction
frequency of occurrence
setting of reaction (e.g. at school or home)
reproducibility of symptoms on repeated exposure
what food and how much exposure to it causes a reaction.
Cultural and religious factors that affect the foods they eat.
Who has raised the concern and suspects the food allergy.
What the suspected allergen is.
The child or young person’s feeding history, including the age at which they were weaned and whether they were breastfed or formula fed – if the child is currently being breastfed, consider the mother’s diet.
Details of any previous treatment, including medication, for the presenting symptoms and the response to this.
Any response to the elimination and reintroduction of foods.
The NICE Clinical Guideline 5715 (atopic eczema in children) recommends that health-care professionals should seek to identify potential trigger factors during clinical assessment including:
irritants
skin infections
contact allergens
food allergens
inhalant allergens.
The Royal College of Paediatrics and Child Health also provides advice on allergy-focused questions to be used when taking a clinical history. An initial screening set of questions is recommended to identify patients, in community settings, for whom a more detailed allergy history may need to be taken. If allergy is suspected, further questions are grouped into six areas:
general history questions asking about general health, current medications, previous allergy testing, lifestyle and general home conditions
general allergy history questions
food-related questions
respiratory-related questions
ear-, nose- and throat-related questions
skin-related questions.
If IgE-mediated allergy is suspected, based on the results of allergy-focused clinical history, NICE Clinical Guideline 1167 (food allergy in children and young people) recommends that the child or young person should be offered a SPT and/or blood tests for specific IgE antibodies to the suspected foods and likely co-allergens. It further recommends that these tests should be undertaken only by health-care professionals with the appropriate competencies to select, perform and interpret them, and should be undertaken only where there are facilities to deal with an anaphylactic reaction.7 The guideline also states that the patient should be given information on when, where and how an OFC or food reintroduction procedure may be undertaken. However, these tests should not be performed in primary care.7
Management
The management of allergy is dependent upon type and severity and many allergies can be managed and treated in primary care settings. More severe allergies and more complex patients may require additional management and referral on to specialist services.
The NICE Clinical Guideline 1167 (food allergy in children and young people) recommends referral to secondary or specialist care when the child or young person has:
faltering growth in combination with one or more gastrointestinal symptoms
not responded to a single-allergen elimination diet
had one or more acute systemic reactions
had one or more severe delayed reactions
confirmed IgE-mediated food allergy and concurrent asthma
significant atopic eczema where multiple or cross-reactive food allergies are suspected by the parent or carer.
Or there is:
persisting parental suspicion of food allergy (especially in children or young people with difficult or perplexing symptoms) despite a lack of supporting history
strong clinical suspicion of IgE-mediated food allergy but allergy test results are negative
clinical suspicion of multiple food allergies.
The NICE Clinical Guideline 57 (atopic eczema in children) and NICE Quality Standard 44 (atopic eczema in children)14,15 both recommend that children with a suspected food allergy should be referred for specialist investigation and management by a paediatric allergist or paediatric dermatologist.
With respect to management following a severe acute episode, NICE Clinical Guideline 13411 (anaphylaxis assessment) recommends that prior to discharge a health-care professional with the appropriate skills and competencies should offer the following:
information about anaphylaxis, including the signs and symptoms of an anaphylactic reaction
information about the risk of a biphasic reaction
information on what to do if an anaphylactic reaction occurs (use the adrenaline injector and call emergency services)
a demonstration of the correct use of the adrenaline injector and when to use it
advice about how to avoid the suspected trigger (if known)
information about the need for referral to a specialist allergy service and the referral process
information about patient support groups.
Treatment
Mild allergies can be treated using over-the-counter medications, such as antihistamines, and simple avoidance of the identified allergen(s).
The NICE Clinical Guideline 1167 (food allergy in children and young people) recommends that, once an allergy is suspected, based on clinical history, information should be provided to the patient about:
type of allergy suspected
risk of severe allergic reaction
potential impact of the suspected allergy on other health-care issues, including vaccination.
If a food elimination diet is advised information should be provided on:
what foods and drinks to avoid
how to interpret food labels
alternative sources of nutrition to ensure adequate nutritional intake
the safety and limitations of an elimination diet
the proposed duration of the elimination diet
when, where and how an OFC or food reintroduction procedure may be undertaken.
The NICE Clinical Guideline 5715 (atopic eczema in children) recommends that health-care professionals should use a stepped approach for managing atopic eczema in children and should tailor the treatment step to the severity of the atopic eczema. Emollients should form the basis of atopic eczema management and should always be used, even when the atopic eczema is clear. Management can then be stepped up or down, according to the severity of symptoms, with the addition of the other treatments such as mild-potency topical corticosteroids (for mild eczema), moderate-potency topical corticosteroids (for moderate eczema), tacrolimus, bandages (for moderate or severe eczema), and potent topical corticosteroids, phototherapy and systemic therapy (for severe eczema only). Very potent topical corticosteroids should not be used without specialist dermatological advice.
In selected patients allergen immunotherapy may be appropriate. It involves the repeated administration, either subcutaneously or sublingually, of allergen extracts. The potential outcomes of immunotherapy are:
reducing allergy symptoms on subsequent allergen exposure
improving quality of life (QoL)
inducing long-term tolerance.
Immunotherapy is time-consuming and expensive, and there is a risk of a severe allergic reaction or anaphylaxis during administration. According to the British Society for Allergy & Clinical Immunology guidelines,17 the main indications for immunotherapy in the UK are:
IgE-mediated seasonal pollen-induced rhinitis, if symptoms have not responded adequately to optimal pharmacotherapy
systemic reactions caused by hymenoptera venom allergy
selected patients with animal dander or HDM allergy in whom rigorous allergen avoidance and reasonable pharmacotherapy fail to control symptoms.
The selection, initiation and monitoring of all patients for immunotherapy should be supervised by specialists in allergy. Immunotherapy should be administered only by physicians and nurses with specialist knowledge of allergy and specific immunotherapy. Immunotherapy is an attractive option for the treatment of food allergies, as its goal is to induce tolerance in the person. With desensitisation, the treated person manifests a decreased response to the allergen.17
Regarding treatment following severe acute episodes, NICE Clinical Guideline 13411 (anaphylaxis assessment) recommends that after emergency treatment for suspected anaphylaxis patients should be offered an appropriate adrenaline injector as an interim measure before the specialist allergy service appointment. An adrenaline autoinjector is a medical device for injecting a measured dose or doses of epinephrine (adrenaline), by means of autoinjector technology. It is most often used for the treatment of anaphylaxis. Most individuals with a severe IgE-mediated food allergy are advised to carry an autoinjector in case of accidental exposure. There are many barriers to the successful use of an autoinjector, including the ability to recognise the symptoms of anaphylaxis, the availability and understanding of how to use the autoinjector, and anxiety associated with its use.
Patient issues and preferences
Allergic reactions can have a daily impact on the QoL of the individual, and can affect their ability to participate in everyday and social activities, perform work-related duties, undertake examinations and pursue their career of choice. The effect of allergies is described in two reports produced by Allergy UK. The Stolen Lives survey found that for 28.4% of respondents allergies had a serious effect on how they planned important life events, and for 26% their allergy severely affected their everyday life.18 The report The Disturbing Impact of Skin Allergy and Sensitivity in the UK report19 states that 78% of respondents suffered from reactions to their skin allergy all year round, and for 62% their condition had stopped them from going out socially and carrying out day-to-day activities.
Where food allergy is diagnosed, implementing special diets for children can also be difficult for families to manage, particularly where there are multiple dietary requirements in one family. A 201020 review on the psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families reported that non-allergic siblings often adopted the restricted diet that the allergic child followed. The same review20 highlighted the effect of allergy on the QoL of patients and caregivers. It reported that allergy heightened patients’ and caregivers’ anxiety because of the need for constant vigilance, particularly in new situations. It also showed that parents tended to be overprotective of children with allergy, particularly those who have had anaphylaxis. There can also be anxiety for a parent or caregiver associated with administering an adrenaline injection.20
