title: Etiology and pathogenesis of adverse drug reactions.
abstract: In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.
authors.affiliation: Department of Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Hausmann
authors.forename: B
authors.initials: B
authors.lastname: Schnyder
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism; D001491:Basophils / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003877:Dermatitis, Contact / Q000209:etiology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology*; D007073:Immunoglobulin E / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D016207:Cytokines; D018836:Inflammation Mediators; D007073:Immunoglobulin E