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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 detailsThe measurement of serum tryptase after allergic reactions remains under-used, even after life-threatening episodes of anaphylaxis. Acute elevation of serum tryptase indicates degranulation of mast cells which occurs either due to an IgE-mediated mechanism, for example with penicillin allergy, or may result from direct degranulation of mast cells through non-IgE-mediated means, for example with NSAIDs or opiates. The rise in tryptase levels starts to be detected in serum within minutes of anaphylaxis but the level will gradually revert to normal over the next 6–24 hours depending on the height of the increase and often correlates with the severity of the anaphylaxis.
Anaphylaxis is a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing life-threatening problems involving the airway (pharyngeal or laryngeal oedema), breathing (bronchospasm with tachypnoea), circulation (hypotension or tachycardia), or a combination of these. In most cases, there are associated skin and mucosal changes. However, some of the symptoms of anaphylaxis may be due to other causes, such as an acute cardiovascular or respiratory event. Therefore, measurement of serum tryptase taken in a timely manner can help to identify whether the cause is due to anaphylaxis and if the level is acutely elevated this should reduce the requirement for unnecessary investigations of other causes. An acute increase in serum tryptase also indicates that the reaction was potentially life-threatening and, therefore, indicates a need to identify the drug that caused the reaction and any potential cross-reacting agents in order to reduce further risk.
7.1. Review question: What is the clinical and cost effectiveness of serum tryptase testing compared with reference standard tests for the diagnosis of an anaphylactic reaction due to suspected drug allergy?
For full details see review protocol in Appendix C.
Table 12
Characteristics of review question.
7.2. Clinical evidence
The utility of serum tryptase for the diagnosis of anaphylaxis has been published in the context of NICE clinical guideline 134: Anaphylaxis (2011).124 We conducted a full search on this topic and identified 159,59 study that was not included in the anaphylaxis guideline and a further study141 published since the guideline which were both added to this review. All studies included in the Anaphylaxis guideline that were not specific to drug allergy were excluded. After this exclusion 2 studies104,112 remained from the Anaphylaxis guideline as well as the additional studies.59,141
Table 13
Summary of studies included in the review.
Evidence was divided by serum tryptase threshold:
- Two studies provided evidence for testing at a medium threshold at peak (11.4 and 12 microgram/litre) and
- Three studies provided evidence for testing at a high threshold at peak (24 and 25 microgram/litre)
Any information about the timing of testing was also summarised and is presented in the GRADE evidence profile (Table 14).
Table 14
Clinical evidence profile: serum tryptase.
Evidence from these studies are summarised in the clinical GRADE evidence profile below (Table 14). 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.
7.3. 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 test is £36.67, therefore the total cost estimate of tryptase testing is £73.34. It is noted that this figure does not capture the full economic impact of tryptase testing, which would include the time of a healthcare professional to administer the tests, as well as downstream cost and quality of life implications of using the tests.
7.4. Evidence statements
Clinical
- Very low quality evidence from 4 observational studies (n=480) showed good level of specificity (89–100% where it was possible to derive this measure) regardless of threshold. Sensitivity was low (median 64% regardless of threshold). There was large uncertainty around the estimate and it is therefore unclear how to interpret this. Information on timing was not available in all studies, but when described peak levels were reached up to 2 hours.
Economic
- No relevant economic evaluations were identified.
7.5. Recommendations and link to evidence
| Recommendations |
Measuring serum tryptase after suspected anaphylaxis
|
|---|---|
| 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). A positive test result (acutely elevated serum tryptase) would be highly suggestive of drug allergy and should direct further investigation. Therefore the specificity of the test result is important, that is, false positive results should be low. For this condition it is also paramount not to miss cases and therefore if a person tests negative on tryptase the probability that he or she had an anaphylactic reaction should be lower. The sensitivity of the test result is therefore also important. However, the GDG agreed that a normal serum tryptase, taken acutely does not exclude drug allergy. Therefore the sensitivity measurement of the test may not be weighted as the most important outcome. |
| Trade-off between clinical benefits and harms | The evidence indicated that the proportion of people who have the condition when they tested positive (PPV) was high. Specificity values were also generally very high (between 89% and 100%). However since sensitivity was variable and modest, many people without elevated levels of tryptase did have anaphylactic reactions due to drug allergy. They would therefore be missed at this time point and might receive the drug again in the future before referral to specialists. Moreover, people with negative tryptase results might wrongly believe that the reaction was unrelated to the drug they had received. |
| 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 GDG concluded that modelling would not be feasible for this review question due to the lack of necessary clinical data linking diagnostic test results with future clinical outcomes such as further allergic reactions, alternative drugs taken, hospitalisation and resource use. The GDG therefore considered the unit costs of these tests and discussed the likely impact on downstream resources and health related quality of life. Mast cell tryptase blood testing has an additional cost, including the analysis of 2 tests (£77) and additional healthcare professional time to collect the samples. Tryptase results are highly useful to GPs and specialists when they are later considering whether a person has a drug allergy and deciding what further tests are required. They are also helpful in informing the healthcare professional on what action should be taken in managing any drug allergy. The GDG believed that correctly administered and reported tryptase testing would be likely to reduce future resource use by reducing the extent of further investigations needed into possible drug allergy in an individual. Tryptase testing would also increase clinicians' abilities to correctly diagnose an individual as having or not having a drug allergy. This could reduce future hospitalisations due to further allergic reactions in those with drug allergy, thereby reducing costs and improving quality of life, and reducing excess spending on unnecessary alternative drugs in those without drug allergy. The GDG therefore agreed that mast cell tryptase testing is likely to be cost effective. For tryptase testing to take place on a routine basis the incorporation of blood sample tubes for tryptase testing into anaphylaxis kits would be an efficient method of ensuring these very low cost items are available to clinicians at the point at which they are needed. |
| Quality of evidence | The quality of the evidence was judged to be very low for all thresholds of serum tryptase. Some studies had poor definitions of the hypersensitivity reaction or recorded time intervals poorly. A variety of different tests was also used (for example, radioimmunoassays (RIA), Immunotech; UniCAP system, Pharmacia) which may also limit the generalisability of these results. The statistical measures did show wide confidence intervals and it is therefore difficult to estimate confidently how accurate the tests were as confidence intervals ranged sometimes from 41% to 83%. |
| Other considerations | Tryptase testing is currently usually carried out in secondary care. Serum tryptase tests will remain stable for 24 hours at room temperature and therefore the GDG considered that it was a suitable test to be carried out within a GP setting and would assist in the future management of the person if referred on to secondary care. The group agreed that the test is currently underutilised within primary care, but needs to be undertaken in a timely manner and records of timings kept in the person's notes. No studies were identified that directly reported evidence for the use of serum tryptase testing in children. The GDG discussed whether any specific recommendations were needed for children and concluded that the recommendations would apply to all age groups. The GDG agreed that sample tubes should be incorporated into anaphylaxis kits and resuscitation trolleys, as this would provide a practical prompt to take a blood sample at the time of the reaction and would make the process easier and quicker. The GDG discussed the timing of tryptase testing with peak elevations usually reported around 1–2 hours after the reaction. The utility of testing beyond 4 hours was debated. One study (Sala-Cunhill et al. 2013141) reported patients with elevated tryptase at different time points beyond 2 hours, but this was in a mixed population of a small group of people with drug allergy reactions. In this study the number of people with tryptase levels recorded later than 2 hours was small (a mixed allergy group of 45 people at 4–6 hours and 27 at 12–24 hours). This indicates that serum tryptase may remain elevated beyond 4 hours, but this study was not large enough to be conclusive. The study reported elevated tryptase in the 1–2 hour timeframe as significantly higher than at any other time point. The other studies all investigated reactions to anaesthesia and did not report any timings other than a 2-hour time point. The NICE Anaphylaxis guideline124 recommends that the test should be carried out preferably within 2 hours and not beyond 4 hours in order to encourage people to carry out the test early. Although a raised tryptase may occur beyond the 4-hour period, this would usually only be in a small percentage of people. The decision around timing of the tests in the Anaphylaxis guideline was made by consensus, and so the GDG discussed whether the same view would be held by health professionals now. The GDG noted that the test was more likely to be done within a shorter time period in a hospital emergency setting, and that after 4 hours the patient may have been moved and so there may be an increased chance the test would not be undertaken at all and cases may be missed. The recommendations for serum tryptase testing in the Anaphylaxis guideline are valid for those with a suspected drug reaction and have therefore been referred to within this guideline. |
- Measuring serum tryptase after suspected anaphylaxis - Drug AllergyMeasuring serum tryptase after suspected anaphylaxis - Drug Allergy
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