ImmunoCAP ISAC 112 for multiplex allergen testing

5.1 The diagnostics advisory committee reviewed the evidence available on the clinical and cost effectiveness of using multiplex allergen testing, in combination with standard clinical assessment, to help diagnose allergy and predict the risk of an allergic reaction in people with allergy that is difficult to diagnose.

5.2 The committee considered the evidence on the 2 different technologies, ImmunoCAP ISAC and Microtest. It noted that 20 publications of 15 studies using ImmunoCAP ISAC met the inclusion criteria for the systematic review and of these, 8 reported diagnostic accuracy but none reported clinical outcomes. No evidence was found for Microtest but the committee noted that this was a new technology so evidence may be available in the future. The committee concluded that there was insufficient evidence to determine the clinical and cost effectiveness of Microtest.

5.3 The committee considered the different versions of the ImmunoCAP ISAC. It noted that evidence on all versions of ImmunoCAP ISAC had been included in the systematic review and that 1 of the 15 studies used the most recent version, ImmunoCAP ISAC 112. The committee heard that all versions were considered because the evidence may provide additional information on current versions and that the versions differed in the number of allergen components that can be detected with the test rather than there being technological differences between the versions. The committee concluded that the different versions are technically comparable but noted that there may be differences in the usability and the clinical and cost effectiveness of the different versions because the more recent versions could detect a higher number of allergen components at the same time.

5.4 The committee considered the quality and generalisability of the studies using ImmunoCAP ISAC included in the systematic review of clinical effectiveness. The committee noted that generally the evidence was of high or unclear risk of bias because there was insufficient detail in the publications. The committee also heard from a clinical expert that there were differences in clinical practice for allergy testing in the NHS compared with the rest of Europe, where most of the studies were conducted, and that as a result some of the studies may not be generalisable to clinical practice in England.

5.5 The committee considered the diagnostic accuracy of multiplex allergen testing using ImmunoCAP ISAC. The committee heard from clinical experts that the gold standard for diagnosing allergy was a double‑blind, placebo‑controlled allergen challenge test. The committee noted that many of the reported diagnostic accuracy studies did not use this as the reference standard, but used a combination of skin prick testing, single specific‑IgE tests and challenge testing as the reference standard. The committee also heard from the external assessment group that many of the studies only reported subsets of the allergen components tested, so overall accuracy figures were not reported. The committee noted that there was considerable variation in the reported sensitivity and specificity values of the ImmunoCAP ISAC, and that there was uncertainty in the level of correlation between ImmunoCAP ISAC and single specific‑IgE tests in detecting the same allergen. The committee concluded that more evidence is needed on the diagnostic accuracy of ImmunoCAP ISAC and single specific‑IgE testing in the same population using an appropriate reference standard.

5.6 The committee considered whether multiplex allergen testing could be used as a replacement for multiple single specific‑IgE tests in certain people. It heard from clinical experts that there were some people in whom the number of allergens that needed to be tested was high enough for it to be cheaper to use multiplex allergen testing rather than multiple single specific‑IgE tests. It also heard that there was considerable uncertainty around the comparability of single specific‑IgE‑test results and those from multiplex allergen testing, and that there is uncertainty in the cut‑off values used for both tests. The committee concluded that more evidence is needed to show if multiplex allergen testing and single specific‑IgE testing are comparable, before multiplex allergen testing could be considered as a replacement test.

5.7 The committee heard from clinical experts that allergy can be difficult to diagnose and manage. The clinical experts advised the committee that an allergy‑focused clinical history is the most important tool in diagnosing allergy and should always be the first step. The committee heard that allergic reactions can vary widely between people and that a person's response to an allergen is not always the same each time, even to the same allergen. It also heard from clinical experts that it can be difficult to identify the causal allergen in some people even after testing and that difficulty in diagnosing allergy is often why allergy is difficult to manage and control. The committee concluded that the benefit of using ImmunoCAP ISAC is most likely to be seen in a tertiary setting in people whose allergy is difficult to diagnose and that in these people, it is likely to be an additional diagnostic tool rather than a replacement for skin prick testing and oral‑food‑challenge tests. The committee also concluded that more clarity on the context, particularly the sequence of testing and the defined population in which ImmunoCAP ISAC would offer most help in allergy diagnosis, would be useful.

5.8 The committee considered the difficulty in interpreting the results of multiplex allergen testing. The committee heard from clinical experts that correct interpretation of multiplex allergen testing results is difficult and must always be done in the context of a complete allergy‑focussed clinical history. The committee heard that multiplex allergen testing results show a pattern of sensitisation. The committee also heard that sensitisations do not always correlate with clinical symptoms and that sensitisations shown on multiplex allergen testing that do not correspond to clinical symptoms could be real sensitisations but of unknown clinical significance. It noted that incorrect interpretation of results may lead to an incorrect diagnosis of allergy, unnecessary restriction of diets, and considerable impact on a person's quality of life. The committee also noted the 2 studies included as examples to show this (see sections 4.29 and 4.30). The committee therefore concluded that multiplex allergen testing results should only be interpreted by an allergy healthcare professional with appropriate expertise in its correct interpretation.

5.9 The committee considered current allergy services in the NHS in England. It noted that there was considerable variation in practice, particularly in primary care and in access to allergy specialists. The committee heard clinical experts share their concern that people are on restriction diets unnecessarily because of a lack of education and training for NHS healthcare professionals in interpreting allergy test results correctly, but also because many people were getting test results through commercial routes and private medical care without support or expertise for correct interpretation of the results. The committee noted that inappropriate allergy testing, particularly using allergy panel tests and multiplex assays, could increase the burden on the NHS because of the high proportion of results that can be incorrectly interpreted by professionals without appropriate expertise and training. It noted that this could lead to long consultations for people who have positive allergy test results to explain the correct interpretation of the results and also, to correct the use of unnecessary restriction diets. The committee also heard from clinical experts that, although there is no published data, in their clinical experience inappropriate use of restriction diets can, in some cases, trigger a real allergy and so should be avoided. The committee noted there is an absence of guidance on multiplex allergen testing and the interpretation of test results, particularly in adults, and concluded that patient and healthcare professional advice is needed on allergy testing to prevent any further increase in the inappropriate use of testing and restriction diets.

5.10 The committee considered the quality control of multiplex allergen testing. The committee heard from experts that there were no reference standards available for component allergens and that getting United Kingdom Accreditation Service (UKAS) accreditation for this test could be difficult. The committee also heard that there are currently no external quality assurance schemes available for multiplex allergy testing. The committee concluded that external quality assurance schemes may need to be considered if multiplex allergy testing were routinely implemented in the future.

5.11 The committee considered the costs included by the external assessment group in the assessment. The committee heard from clinical experts that the cost of £570 for an oral‑food‑challenge test, which was used in the base‑case analyses, was too high and not representative of the cost of oral‑food‑challenge tests in NHS practice. It heard from the external assessment group that the high cost included the cost of a hospital appointment to implement the food elimination diet before the oral‑food‑challenge test. The committee heard from clinical experts that this appointment is not part of the current care pathway. The committee concluded that the cost of £256 used in the scenario analyses, rather than the £570 used in the base‑case analyses, is more likely to represent the cost of an oral‑food‑challenge test in the NHS.

5.12 The committee considered the cost effectiveness of multiplex allergen testing. It noted that because of a lack of clinical data, the external assessment group could not develop a de novo economic model but instead developed a conceptual model that showed the data and parameters that are needed to inform a cost‑effectiveness analysis. It also noted that the external assessment group carried out 2‑way threshold analyses and scenario analyses based on theoretical assumptions to show the potential cost savings by introducing multiplex allergen testing. The committee concluded that there was too much uncertainty in the potential cost savings to be confident that they would be realised in practice and more evidence is needed.

5.13 The committee discussed the challenges of research into diagnosing allergy. It heard that funding for research into allergy testing is limited and that ideally a study would investigate allergy testing in a large unselected population with allergy. The committee noted that this could be difficult to do because of the heterogeneity and complexity of the population with suspected allergy, but concluded that these difficulties could be minimised if the population and the context in which multiplex allergen testing should be used were clearly defined.