DRESS/SJS/TEN (severe DHR) and HLA-linked DHR are p-i. Initially it was thought that p-i reactions were the exception while the hapten mechanism represented the main cause of systemic T cell mediated DHR. Conversely it seems to be the opposite as p-i appears to be the main mechanism in T cell mediated DHR: Whenever the mechanism was investigated how drugs cause severe DHR (DRESS, SJS/TEN), it was always found to be due to p-i.
It is unclear whether the majority of severe MPE is due to p-i. As the in vitro analysis of amoxicillin induced MPE (analysis of >150 amoxicillin induced MPE) regularly reveals high secretions of IL-5, IL-13, IFNg, granzyme B and granulysin upon drug exposure (very similar to DRESS cases), the in vitro drug stimulation in MPE is often strong and includes the secretion of Th1, Th2, and cytotoxic cytokines simultaneously. It is actually often stronger and broader than the cytokine secretion upon tetanus control, and is reminiscent of an in vitro mixed leukocyte reaction (MLR). Further work is needed, but most MPE appear to be mediated by p-i.
Importantly, all drugs which develop DHR and have a strong HLA-linkage (e.g. allopurinol/oxypurinol and B*58:01) stimulate via p-i. Protein reactions are not HLA restricted: A protein is large and is processed into various small peptides. These peptides (including the hapten-modified peptides) fit into different HLA alleles and not in only one HLA like observed with drugs. Thus, the DHR-HLA linkage seen with certain drugs can only be explained by direct drug binding to an allele-typic region of the HLA-molecule. This was also confirmed in structural and computational studies. Importantly, if a drug can be stimulatory by p-i or by hapten mechanism (SMX/SMX-NO, beta-lactams), the severe T cell mediated symptoms are mediated by p-i and are HLA-allele restricted, while the hapten-reactions are not. Thus, the list of drugs acting via p-i and causing DHR is now longer than the list of hapten-like drugs (table).
First hapten, then non covalent drug binding: A strong argument for a hapten-mechanism underlying DHR was the ability of the drug to cause all, namely IgG, IgE and T cell mediated DHR, since these different immune reactions required the immunogenic presentation of the drug in various ways. This is best achieved using hapten (and thus antigenic) features of a drug. Indeed, the classical hapten-drugs beta-lactam antibiotics, SMX-NO, or PPI are able to induce all forms of Gell and Coombs immune stimulations, while e.g. classical and exclusive p-i drugs like carbamazepine or abacavir induce only T cell reactions, but never anaphylaxis. Importantly, an ability to act as hapten does not rule out that non-covalent binding like in p-i plays a role in DHR. Actually, during a DHR the type of drug-protein binding may change: A drug may act as hapten in the induction phase causing asymptomatic immunity, but the effector mechanism of immunoglobulin-reactions and some severe T-cell mediated DHR may actually be due to non-covalent drug bindings. Thus, beta-lactam antibiotics – the classical hapten-drugs - are the main elicitor for "fake antigen" reactions, drug induced immune thrombocytopenia (DITP) and p-i stimulations, which are all based on non-covalent drug-protein interactions and are not antigen induced.
The polyclonal T cells response stemming from the memory T cell pool includes T cells which are primed by prior immune responses. An important role play herpes viruses (HHV6, CMV, EBV, Herpes simplex I), where a relatively large amount of T cells are involved in the control of these herpes viruses. Indeed, herpes virus reactivation is so common, that it is part of the Japanese definition of DRESS.  Since the precursor frequency of such herpes virus specific T cells is high (up to 10% of the CD8+ T cells in the elderly can be devoted to herpes virus control, symptoms due to such T cells appear already after ca. 2–6 weeks.