Immunologically-mediated specific reactions
These reactions are classified into immediate reaction (IR) and non-immediate reactions (NIRs) depending on whether they occur within 1-6 hours or later after the drug intake. The first group is mostly associated with an IgE-mediated mechanism and the latter with a T-cell dependent type.191,192
Skin tests (STs) are useful biomarkers for IRs to beta-lactam (BL) .14,191-194However, their sensitivity based on the classical antigenic determinants has decreased over the last decades195 possibly due to the changing patterns of consumption (e.g. amoxicillin-clavulanic acid is replacing penicillin).193 Interestingly, one antigenic determinant recognized by most patients with confirmed reactions to clavulanic acid has been recently identified.196Therefore, amoxicillin and any suspected BL must be included when performing STs.192,195,197,198 For other drugs and for NIRs, the value of STs is very limited.14,192,193,199
Regarding in vitro tests, during the acute phase of the reaction, serum tryptase is the most valuable biomarker for confirming mast cell activation in IR.191 The expression of granzyme B and granulysin in blood cells may be useful for detecting lymphocyte activation in severe NIR.200 At the resolution phase, immunoassays are used in IRs to determine sIgE, although the sensitivity is lower than for STs191,201,202 and only commercially available for limited drugs. For BLs, it shows a variable sensitivity (0-50%),191,192,201 with the possibility of inducing false positive results when testing for Penicillin-V.203 The value of BAT in IR has been proven for BL and quinolones, giving a sensitivity up to 55%204,205 and 83%,199,206respectively. The sensitivity of both sIgE and BAT correlates with severity reaction201, decreases with time,205,207 and depends on the activation basophil marker assessed, e.g. the detection of CD203c increases BAT sensitivity although remaining low (36.4%).206,208
The value of lymphocyte transformation test (LTT) in NIRs has shown to be unsatisfactory.14,191 The Tim3/galectin-9 axis functions as a checkpoint inhibitor for Th1 cells. Interestingly, Th1 cells and dendritic cells of patients with drug-induced maculopapular exanthema expressed lower levels of Tim3/galectin-9 at baseline compared with tolerant individuals.209 This observation might help identify subjects at risk of NIRs.