Recognition, assessment, and management of coeliac disease: summary of updated NICE guidanceBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4513 (Published 02 September 2015) Cite this as: BMJ 2015;351:h4513
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In response to Maher et al. the Guideline Development Group (GDG) were aware of the debate between clinical immunologists in the field about appropriate testing standards and received feedback regarding this at consultation; this is elaborated upon in the evidence to recommendation section of the full guideline.
The GDG discussed this issue and their advice was that all of the IgA anti-tTG assays currently in use were developed and validated as assays to detect serum levels of IgA against tTG, where tTG is the antigen. None of these IgA anti-tTG assays were developed and validated to detect total serum levels of IgA, where IgA is the antigen. The use of IgA anti-tTG assays to triage samples for total IgA testing based on the detectable IgA anti-TTG antibody level is the incorrect use of the IgA anti-tTG assays. Using IgA anti-tTG assays to detect a different antigen (IgA) could increase the false-positive rate of the IgA anti-tTG assay. Using the IgA anti-TTG assay in this way relies on the background of the assay and the assumption is that all the background is due to IgA; however this is not the case – the background may be due to rheumatoid factor or due to slightly haemolysed samples.
The paper cited is a case report of a 'serendipitous' detection of a rare immunodeficiency, which does not support the case that 'individuals with detectable IgA anti-TTG antibodies are unlikely to be IgA deficient' and the case discussed did not have detectable IgA anti-TTG antibodies. The case supports reasonable substantiation of the GDG's suggestion that the routine quantitation of serum IgA may have collateral benefits in the identification of immunodeficiencies.
In relation to interpretation of the ISO15189 standards and their application in practice, the GDG's view was that, where a commonly available test has been designed and validated for a particular purpose, it will very seldom be appropriate to rely on an alternative test to derive the same results. It may be that individual laboratories are able to demonstrate adequately validated alternatives to tests that are designed for a particular purpose in line with the standards.
The cost of total IgA testing was not included in modelling the cost-effectiveness of serological strategies, apart from the test’s low absolute cost, as all strategies considered contained an IgA component. In the analysis of which serological test to use in people with symptoms suggestive of coeliac disease, adding a cost (of total IgA) to each strategy would have no influence on the relative cost-effectiveness of the various approaches. However in the analysis of whether to test (in the context of active case finding) an underestimation of the IgA test cost may slightly exaggerate the cost-effectiveness of serological testing in the groups considered.
We agree that the potential for valuable incidental findings are a collateral benefit of measuring IgA levels, and no substitute for appropriate diagnostic process in people suspected of immunodeficiency. However, the GDG noted that, in their experience, suspicion can be raised in this way, and this is an indirect benefit of the approach that should not be completely discounted.
We review our guidelines for update regularly and have passed your comments have been passed to the surveillance review team for consideration at the next review.
Competing interests: No competing interests
Downey et al. (1) succinctly summarise the recently updated guideline from the National Institute for health and Care Excellence (NICE) for the recognition, assessment and management of coeliac disease (CD) (http://www.nice.org.uk/guidance/ng20, accessed October 30th, 2015). NICE continue to recommend that laboratories should test for total IgA and IgA tissue transglutaminase (tTG) antibodies as the first choice investigation in children, young people and adults. At first sight, the underlying rationale for this guidance is logical since it is intuitive that deficiency of IgA may lead to false negative testing using this approach.
Reduction in serum levels of IgA is most commonly of primary rather than secondary origin and may be considered in two settings. The first of these is selective IgA deficiency (sIgAD), which is defined by a serum IgA level that is below the limit of detection (0.07g/L in most diagnostic laboratories; not 0.07mg/L as indicated by NICE). Owing to the physiological delay in maturation of IgA levels, sIgAD should be diagnosed after the age of 4 years and is accompanied by normal levels of IgG and IgM (2,3). In Caucasians, sIgAD affects 1 in 600 individuals, rendering this the most common primary immunodeficiency disorder (4). This condition is significantly more frequent in patients with CD, in whom a prevalence of up to 3% has been reported (5). In this setting, use of IgA-based screening tests such as IgA tTG is generally but not always (6) invalid and IgG based assays as IgG tTG may be positive, assisting in the screening process (7). By contrast, partial IgA deficiency (pIgAD) is characterized by low but detectable serum IgA levels that do not fulfill the criteria for sIgAD (8). This finding is observed mainly in children below 5 years, about half of whom will “catch up” to attain normal circulating IgA levels by age 14 (9). Occasionally, pIgAD deficiency may compromise the sensitivity of the IgA tTG screening test (5,10), although most studies report robust performance of the IgA tTG assay in this setting (11-13). This is an important issue since approximately 10% of individuals tested for CD have serum IgA levels that are below the appropriate age-stratified normal range (13,14).
The National Health Service faces spiralling funding pressures, mandating increasing efficiency savings. Consequently, there is a need to continually question the cost/benefit ratio of routine testing algorithms in all aspects of clinical practice. The absolute need for serum IgA testing accompanying all CD screening tests has been questioned for many years (15,16). More recently, an economically favourable solution has been identified to allow the detection of pIgAD/ sIgAD with the demonstration that serum IgA levels are proportional to the background signal generated in the IgA tTG assay. Initial studies using IgA tTG ELISA assays demonstrated the principle that identification of a low optical density in the assay could be used to pinpoint samples more likely to contain reduced levels of IgA (17-19). More recently, the same principle has been demonstrated in other commonly used solid phase assays that detect IgA tTG antibodies (20-22). In-house validation of such an approach enables laboratories to identify that subset of samples in which quantitative serum IgA testing is required. Such an approach has eliminated the need for serum IgA testing in over 80% of test requests (14). At Barnet hospital, we undertake approximately 9000 CD screening tests each year. Measurement of serum IgA costs £5 per test, meaning that implementation of the NICE guidance would cost an additional £36,000 per annum, approximately. Routine measurement of serum IgA also frequently uncovers elevated levels of this antibody, which may lead to unnecessary additional testing and wasted time for laboratory and clinical staff. We suggest that NICE need to provide additional justification for this point of guidance as a sensible use of limited resources.
1. Downey L, Houten R, Murch S, et al. Recognition, assessment, and management of coeliac disease: summary of updated NICE guidance. BMJ 2015;351:h4513.
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Competing interests: No competing interests