One recurring theme across all twenty-two papers included was that there was a significant RoB through patient selection (Figure 2). The majority of papers only included final results on patients with definite immediate allergy compared to control groups with no history of allergy and able to tolerate oral penicillin. This aids clarity in understanding what a diagnostic test is showing, but it is not applicable to clinical practice, where indeterminate results and alternate diagnosis, such as delayed drug hypersensitivity and chronic spontaneous urticaria, complicate the clinical picture. Future work to overcome this issue should be undertaken, with prospectively collected consecutive samples from participants with suspected penicillin allergy who undergo the gold standard specialist work up.
It should also be noted that as we did not have access to individual data sets, we were unable to adjust for covariates or predictors which may have influenced results. Due to the significant heterogeneity in reporting of potential explanatory variable that may have influenced study outcomes across the manuscripts, we did not perform a meta-regression analysis. This may have identified further bias.
Another limitation is that, while many of the studies confirmed that patients were classified according to the EAACI or ENDA guidelines, not all participants will have had exactly the same assessment. DPT is felt to be the closest to a “gold standard test”. However, given that the risk of anaphylaxis increases to 6% for patients with a history of anaphylaxis to penicillin (12), it is not appropriate to undertake DPT in most high risk cases. Furthermore, it is now well documented that skin testing can also lead to false positives with a recent meta-analysis reporting a summary sensitivity of 31% (95% CI, 19%-46%) and a specificity of 97% (95% CI, 94%-98%), (8). There was also significant heterogeneity in the definition of an “immediate reaction”, with definitions ranging from less than 30 minutes (31, 36), to those occurring up to 24 hours (52), after drug administration.
The majority (91%) of these participants were recruited from Allergy Centres, when they have had an outpatient referral for assessment. While there has been work looking at de-labelling inpatients with DPT, no studies reported BAT results from an inpatient setting. Future work is required to explore if BAT can be used in different clinical settings, such as an emergency department, or in other outpatient facilities other than a highly specialised allergy clinic.