Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe multi-organ drug hypersensitivity reaction (DHR) involving T cells. DRESS patients have a heightened risk (~25%) of developing multiple drug hypersensitivity (MDH) to unrelated drugs from the first reaction. This project aims to characterise DRESS, focusing on those with and without MDH, to identify potential biomarkers for further drug reactions. Methods: This multicentre cross-sectional study analysed clinical features and immune responses, including T cell activation and in vitro cytokine secretion using Cyto-LTT. The study included 20 DRESS patients (12 with MDH), 8 maculopapular exanthema (MPE) patients (4 with MDH), and a control group of 9 healthy donors (HD). Clinical assessments included detailed histories, skin testing, and the RegiSCAR score for diagnosing DRESS. Results: The Cyto-LTT improved diagnostic sensitivity, particularly in DRESS patients, identifying 19% of drugs that were negative by skin testing. MDH patients’ leukocytes exhibited stronger and broader secretions of cytokines and cytotoxic mediators, up to ten-fold higher compared to DHR patients with a single drug sensitisation. T cells from recovered delayed DHR patients exhibited signs of chronic activation after resolution, with elevated CD69 and PD-1 but reduced CD38 and OX-40 levels compared to HD. Conclusion: Recovered delayed DHR patients display an altered T cell activation profile suggesting a “chronic disease” state, possibly explaining the heightened risk of MDH. Increased cytokine secretions, such as stimulation index > 10, especially for cytotoxic mediators, may differentiate those at risk for MDH.

The new nomenclature by the EAACI – was drug hypersensitivity (p-i) forgotten?The EAACI position paper on nomenclature by M Julel(1) is coauthored by 40 (!) scientists and addresses many old and new concepts in connection with allergic and hypersensitivity diseases with the aim to better define and categorize them. Such an undertaking must rest on solid facts and should not omit crucial findings.Immune stimulation by antigen or not? The authors are focusing on classical, antigen (protein) driven reactions, which are developing based on an interplay of dendritic cells, lymphocytes and other cells to handle an antigen and to react to it (1). Although the authors claim to include drug hypersensitivity (DH), they completely omit the fact that drugs can stimulate the immune system in an alternative, unorthodox way (“p harmacological interaction with i mmune receptors”, p-i concept)(2-4). Thereby an initial off target activity of a drug with certain structures of TCR or HLA is followed by complex immune activations, which can result in inflammatory reactions manifested as exanthems, DRESS, SJS/TEN, AGEP (2-4). Various types of p-i can occur together (3, 5).Problem of cytotoxicity : the cytotoxic functions of T cells as an own category (formerly G&C Type IVc) is omitted and handled as part of a type IVa/T1 reaction: This is problematic:Cytotoxicity plays a role in all T cell mediated DH (exanthema, DRESS, AGEP, SJS/TEN) (2, 3) and is often associated with massive eosinophilia (e.g. DRESS). Why is this so? The reason is that both, cytotoxicity and eosinophilia, do NOT arise from a classical antigen driven mechanism (3, 5). E.g., the eosinophilia in DH is not due to the development of a classical Th2/IVb reaction, but is due to a certain type of p-i, which results in massive IL-5 production (5).The unusual induction of cytotoxicity in DH includes also CD4 cells, which are the predominant cytotoxic cells in drug induced exanthema (2). Thus, cytotoxicity in DH is not restricted to CD8 and NK cells, as stated (1).Analysis of drug specific T cell clones has revealed that many are cytotoxic, but do not secrete IFNg, or vice versa, many IFNg producing T cells are not cytotoxic.New classification: The 1967 nomenclature by G&C promoted an unknown area (immunology) into the clinic; the revised version (G&C I-IV a, b, c, d; (2)) connected T cell reactions with activation of inflammatory cells and different clinical pictures and thus helped to better understand different forms of DH. The proposed new nomenclature (1) tries to combine quite different topics like immune reactivity (I-IV), disposition (V, VI) and pharmacological/toxic actions (VII). Actually, types I-IVabcd(2) were only slightly changed (→ I-IVa,b,c) in(1). Thereby the use of the same label (e.g. IVc) for different manifestations (IVc for cytotoxic reactions in(2), but neutrophilic in (1)) programs for misunderstandings.The main problem of (1) is that unorthodox immunity (p-i) was omitted, and thus DH cannot be explained or classified. As discussed (6), DH like ACD can rely on classical immunity like formation of drug/hapten protein complexes (= a new antigen) and such reactions follow G&C I-IV; But the majority of DH are due to unorthodox immune reactions (different forms of p-i(3-5)), which do NOT follow G&C! They are labelled separately (4-6), and these unorthodox immune reactions are actually the main reason why G&C needs to be revised(5, 6).In summary, although DH may not be the main interest of many allergologists, the omittance of unorthodox immune stimulations (p-i) in an official EAACI nomenclature paper, claiming to cover allergy and hypersensitivity, is not understandable. It should be clearly stated that this position paper (1) addresses only antigen reactions but not unorthodox ways of immune stimulations (DH). Surely, unorthodox immune stimulations by drugs, known since > 20 years (2), are still a difficult topic and needs education – but just ignoring these findings is no solution.Hoping that this critic is considered helpful;Best regardsWerner J PichlerADR-AC; Holligenstr 91, CH 3008 Bern, SwitzerlandP.S:The references (e.g. nr 74) do not correspond to the text; this needs to be corrected;Legend fig 5/line7: ….in a process called \southarmonization haptenation

Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i) : drugs tend to bind to proteins and may even bind to immune receptors. In the absence of viral infections, this low affine binding may be insufficient to elicit T cell activation. During a viral infection immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T cell activation and symptoms. There is a situation, where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally acvitates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity with killing of herpes peptide-expressing cells and release of herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.

Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in-vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC-unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. b) Some non-covalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-carrier adducts. Such drug-protein complexes represent so-called “fake antigens”, as they are unable to induce immunity, but may react with and crosslink preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.