Discussion

Recently, the voices in the allergy community have been growing louder favouring a turn away from the classical allergological approach including in vitro plus skin tests putting DPT at the end as the final method and instead heading to a direct DPT without prior testing. This has been propagated especially in the United States (13, 18, 19). With our study, we would like to stress the point, that aiming for such an extreme standpoint puts patients at unnecessary risks while roughly a third of DHR cases can be solved with a safer and cheaper approach.
It may be argued that looking at sIgE and skin tests separately results in only low positivity rates and that these tests may be regarded as dispensable, therefore. Rightly, the low rate of 4.3% drug-specific IgE to β-lactams on the ImmunoCAP® system nearly replicated the 3.4% that we had already described 14 years ago (29). However, these tests are cheap and can be applied on a large patient group (14). Tweaking read out parameters such as lowering the threshold to 0.1 kU/l could have doubled or calculating sIgE/total IgE ratios could have even quadrupled the positivity rates in our patients, but this would have come at the price of a lowered specificity (25). Basophil activation tests are reported as having superior sensitivity and specificity (30, 31). However, they are more expensive, require especially trained personal, expensive laboratory equipment and consume a lot of laboratory time. This makes them a difficult system for use on a broader routine dimension.
Positive skin tests in our study occurred nearly in twice as many patients (7.8%) than drug-sIgE (4.3%). Generally, skin tests tend to be more sensitive than blood tests at an also high specificity with good negative predictive value (32). Our study underlines the role of skin testing and we performed them successfully even in 98 children ≤10 years. However, also their specificity had been challenged (33) while later studies confirmed the high specificity of IDTs especially to cephalosporins (34). IDTs are the most useful skin tests with early and late readings. They cause a little bit of pain, which is usually tolerated by all patients, and they are safe as we experienced no systemic reaction in 1697 IDTs. When a late reading of the IDT is available, PTs added only little additional value and might be omitted in the routine setting. Still, PTs to β-lactams may have a role in the history of severe cutaneous adverse reactions or in other situations, where IDTs are impossible due to patient-specific factors.
Interestingly, the higher rate of confirmed reactions to cephalosporins was just based on the immediate reaction pattern. This had already been described by Romano et al. who confirmed a lot of immediate but hardly any delayed type reactions by skin testing (35).
DPTs are the golden standard to rule out or confirm a DHR (36, 37). This is especially true for the non-immunologically mediated reactions to non-steroidal anti-inflammatory drugs (38). While representing the gold-standard, they are not perfect tests, as numerous studies described false-positive reactions even upon placebo tests (29, 39) and false-negative tests (40). DPTs put patients at risks, are an expensive and resource-consuming measure and are a limited resource, even in well-developed health care systems. In Austria, one of the top-ten countries concerning access to healthcare (41), there is currently no reimbursement scheme for DPTs neither by public nor private healthcare insurances. Because of this lacking financial incentive for hospitals and outpatient facilities, Austria is faced with scarce resources for performing DPTs. The metropolitan area of the Austrian capital city Vienna counts around 3 million inhabitants. Four dermatological and two paediatric wards are the only institutions offering DPTs with a long waiting list. In a personal communication with these institutions, the yearly capacity turns out to be at an astonishingly low 465 DPTs / year. The majority of these (300) are offered by the department of dermatology at the Medical University of Vienna. In an own reference study at this institution (29), only 130/291 (44.7%) DHR evaluations were reserved for antibiotics, the rest for other drugs e.g. NSAIDs. Assuming, that this ratio has not changed much over time, the yearly capacity for performing DPTs with antibiotics in greater Vienna can be estimated at around 207/year. Of the 932 patients in our 2-year study, 37.1% of the cases were solved by the application of the diagnostic algorithm with a clear yes/no outcome. While these 346 individuals already received an allergy passport (27) or the instruction that they can safely re-introduce β-lactams in their antibiotic regimen, the majority of 62.9% cases remained unsolved with an ongoing need for DPTs. These 586 patients/2 years (=269/year) of our single allergy outpatient clinic alone, would have greatly overwhelmed all DPT capacities of Eastern Austria. To up the ante, there are 4 additional Viennese allergy outpatient clinics and many more specialists for dermatology and paediatrics who see additional cases. Hence, the full conventional allergy workup of an allergy outpatient clinic can help to reduce the pressure on underpowered DPT capacities.