I) Is re-exposure to the incriminated drug possible after the
viral infection has disappeared?
This refers to the importance that the viral infection has played in the
DHR, and questions whether the drug-directed T cell response would be
potent enough to occur in the absence of viral infection. This may
critically differ depending on the type of T cell response involved,
i.e., whether it is hapten- or p-i-induced.
So far, it is unclear whether hapten- or p-i- induced DHR are longer
lasting. In hapten responses, the co-stimulation is mainly required for
initiation of a classical T cell response [30]. A certain memory T
cell response, which is less dependent on co-stimulation, might develop
[64]. Thus, the re-exposure to the drug/hapten alone might be
sufficient for the reactivation of memory T cells, suggesting that at
least some classical hapten-reactive T cells may be restimulated even in
the absence of virus co-stimulation.
In p-i reactions, co-stimulation is of less importance [9, 10]. The
viral infection increases the frequency of p-i interactions and results
in a higher affinity of p-i, which is limited to the time of virus
infection. After the elimination of viruses, the in vivoconditions return to normal. This reduces the frequency of drug-immune
receptor interactions and may be insufficient to cause
clinically-important T cell stimulation. This dependence on higher
expression of TCR/HLA would also explain why sensitization during skin
tests is often absent. However, this scenario may only apply to low
affine p-i interactions. During high affine p-i stimulations, the DHR is
more severe (SJS/TEN, DRESS) and less dependent on viral enhancement.
Thus, they may occur without viral co-stimulation. Indeed, a
long-lasting reactivity is well documented for DRESS [66].
The severity and duration of cutaneous symptoms, as well as the presence
of systemic symptoms, may impact whether a DHR can re-occur without
viral infection [38]. An extensive exanthem and prominent
blood eosinophilia may be indicative of a substantial drug-specific T
cell expansion due to high affine (strong) p-i or extensive hapten
reactions and potent downstream IL-5 production. The pool of
drug-specific T cells may persist and the DHR reappears upon drug
re-exposure, even in the absence of virus co-stimulation. On the other
hand, Caubet JC did not find a relationship between the severity of
exanthems to positive provocation tests, but the number of positive
provocation used in this study was small [2]. Alternatively, if the
DHR symptoms were mild even in the presence of viral infection, they
might not re-appear upon re-exposure to the drug without virus
infection. Therefore, there would be no reason to withhold beta-lactams
(or related drugs) in the future.
To add further complexity, p-i- and hapten-induced T cell responses in
the context of viral infections are not mutually exclusive. β-lactams,
for instance, can stimulate the immune system not only by forming an
antigen, but also by stimulating via p-i [68]. Viral infections
enhance both classical antigen stimulation and unorthodox p-i
stimulation by β-lactams, which may explain the high incidence of
β-lactams in virus enhanced DHR.