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.