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.