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National Clinical Guideline Centre (UK). Drug Allergy: Diagnosis and Management of Drug Allergy in Adults, Children and Young People. London: National Institute for Health and Care Excellence (NICE); 2014 Sep. (NICE Clinical Guidelines, No. 183.)
Drug Allergy: Diagnosis and Management of Drug Allergy in Adults, Children and Young People.
Show detailsIn this section we have considered the clinical and cost effectiveness of serum specific IgE testing for the diagnosis of drug allergy. Serum specific IgE testing is only available for reactions to a limited number of drugs, including: amoxicillin, ampicillin, cefaclor, chlorhexidine, morphine, penicillin and suxamethonium. The sensitivity and specificity of each of these tests in predicting whether a patient with a history of drug allergy is either allergic or non-allergic have been considered in order to evaluate whether this test could be used within a non-specialist setting such as a GP's surgery. This is the only non-acute test that can be undertaken in a non-specialist setting. For alternative tests such as skin prick testing or drug challenges the individual would need to be referred to specialist drug allergy services for investigation.
8.1. Review question: What is the clinical and cost effectiveness of serum specific IgE testing compared with reference standard tests in the diagnosis of drug allergy for the following drugs?
- amoxicillin
- ampicillin
- cefaclor
- chlorhexidine
- morphine
- penicillin G
- penicillin V
- suxamethonium
For full details see review protocol in Appendix C.
Table 15
Characteristics of review question.
8.2. Clinical evidence
We searched for diagnostic cohort and case–control studies as well as case series for the utility of serum specific IgE testing. Fourteen studies were identified for this review.17,48,49,54,63,84,85,95,137,144,145,150,166,170 Evidence from these papers is summarised in the clinical GRADE evidence profile below (Table 17). See also the study selection flow chart in Appendix E, sensitivity and specificity forest plots in Appendix J, study evidence tables in Appendix H and exclusion list in Appendix K.
Table 16
Summary of studies included in the review: beta-lactam antibiotics.
Table 17
Clinical evidence profile: serum specific IgE – beta-lactam antibiotics, neuromuscular blocking agents, chlorhexidine.
The evidence in this review is presented by class of drug as follows: beta-lactam antibiotics, neuromuscular blocking agents and chlorhexidine.
The IgE tests used and the study populations were variable and therefore a diagnostic meta-analysis was not carried out. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) criteria.
8.3. Economic evidence
Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
Unit costs
Costs from the Protein Reference Unit in Sheffield71 are used as example costs: the cost per allergen-specific IgE test is £14.30. It is noted that this figure does not capture the full economic impact of IgE testing, which would include the time of a healthcare professional to administer the test, as well as the downstream cost and quality of life implications of using the test.
8.4. Evidence statements
Clinical
Serum specific IgE – beta-lactam antibiotics
- Very low quality evidence from 11 observational studies (n=1624) indicated very variable results in terms of sensitivity and specificity. Specificity was generally higher than sensitivity indicating that the test is better at ‘ruling in’ than ‘ruling out’ beta-lactam allergy. However, imprecision was too high to draw clear conclusions about the test accuracy of this test.
Serum specific IgE – neuromuscular blocking agents
- Very low quality evidence from 2 observational studies (n=461) indicated relatively high levels of misclassification with sensitivity 84% and specificity 75%. The confidence region was large and only 1 result could be clearly extracted. It is therefore difficult to draw clear conclusions about this test in clinical practice.
Serum specific IgE – chlorhexidine
- Very low quality evidence from 1 observational study (n=22) indicated high levels of test accuracy. However, the number of participants in this study was small and it is therefore unclear whether this result is representative until further research is conducted.
Economic
- No relevant economic evaluations were identified.
8.5. Recommendations and link to evidence
| Recommendations |
Measuring serum specific immunoglobulin E
|
|---|---|
| Relative values of different outcomes | The following outcomes were identified by the GDG as important for decision-making: pre-test probability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number of cases missed (false negatives), number of cases mislabelled (false positives). The rate of false negatives represents the proportion of people with a drug allergy in whom allergic reactions will be missed by serum specific IgE testing; the GDG considered this outcome to be significant. Test sensitivity (the proportion of people with drug allergy who have a positive test) is therefore also an important outcome. However, the group also agreed that specificity is important in order that people who do not have an allergy do not falsely receive a positive test result and as a consequence no longer receive the drugs they require or are switched to less effective medication. |
| Trade-off between clinical benefits and harms | The GDG agreed that many people with penicillin allergies will receive false negative IgE test results. The evidence was consistent with low levels of diagnostic test sensitivity shown. The group acknowledged that for beta-lactam antibiotics IgE testing has poor negative predictive values, and there was concern that people with suspected drug allergies may be falsely reassured. However, specificity and positive predictive values were on the whole higher indicating that people who do not have drug allergies would have a high probability of having a negative test, and conversely a high percentage of people with a positive test result go on to be diagnosed with drug allergy. There was less evidence on testing for neuromuscular blocking agents or chlorhexidine. However, studies reported better sensitivity and negative predictive value results compared to IgE testing for beta-lactams. This seems to suggest that fewer people are missed by using serum specific IgE in these cases. |
| Economic considerations | No relevant economic evidence was identified. The GDG identified diagnostic tests (serum tryptase and serum specific IgE) as the second highest priority area for original economic analysis. However, the poor diagnostic accuracy shown by IgE testing in the clinical evidence for this review meant that economic modelling, even if feasible, was not necessary for the GDG's decision-making and so original analysis was not conducted. Carrying out this test incurs costs associated with the time of a GP or nurse, the laboratory test itself, and follow-up appointments. The clinical evidence reveals low sensitivity and specificity values of serum specific IgE tests, and therefore the results of these tests are not deemed a sufficient result on which to base a diagnosis of drug allergy. The GDG were particularly concerned with the high levels of false negative results revealed by the clinical evidence. False negatives could lead to repeat reactions, which in turn have a high cost (emergency admission) and a significant impact on quality of life. False positive results could also have an economic impact, as a person may unnecessarily receive an alternative drug when a drug is needed in future. Alternative treatments are generally less effective and sometimes more expensive than first-line treatments. These economic considerations need to be balanced against the potential benefit from obtaining a true result. If the results of the test could be relied upon, people receiving a true positive result could take up an appropriate management strategy and the cost of referral would be saved. Likewise, true negatives would not need to avoid the drug in question any longer. However, the clinical evidence has revealed such inaccuracy in the test results that the results of serum specific IgE tests cannot be considered conclusive. Diagnoses cannot be based on this test alone regardless of the outcome, and therefore the additional cost of these tests is an inefficient use of resource. The GDG therefore agreed that serum specific IgE tests are unlikely to be cost effective when used on their own in a non-specialist drug allergy setting. |
| Quality of evidence | Quality was assessed as very low for all evidence (serum IgE testing for beta-lactams, neuromuscular blocking agents or chlorhexidine). This was mainly due to the heterogeneity of study populations, type of test used, type of allergy and imprecision of the accuracy measures. Many studies also did not use a gold standard (drug provocation test) as a reference point. As the evidence came from highly selective populations the GDG agreed that it was difficult to extrapolate results to the whole population of people with drug allergies and were therefore cautious about making specific recommendations. |
| Other considerations | The GDG agreed that these tests do not have proven utility in primary care as results could be open to misinterpretation due to poor sensitivity. Additionally the tests do not add much to diagnosis made from a clinical history. The group recognised that in a specialist setting this test would not be used in isolation but may be used in addition to a skin prick test and the clinical presentation. The group noted that many allergic drug reactions are not IgE-mediated and the tests do not include all immunoreactive epitopes. The GDG noted that RAST (radioallergosorbent test) is an old technology and no longer used. None of the studies addressed testing in children and none were conducted in primary care settings. The GDG noted that serum specific IgE for diagnosing drug allergy may be useful in the specialist setting in conjunction with clinical history and other allergy investigations. |
- Measuring serum specific immunoglobulin E (IgE) - Drug AllergyMeasuring serum specific immunoglobulin E (IgE) - Drug Allergy
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