Immunological drug reactions

"Bizarre" hypersensitivity reaction to medicinal products; unexplained due to pharmacological property; (unforeseeable or unexpected) adverse drug reaction. Such reactions occur only in specially predisposed patients. The immunological reaction types are divided into Type I - Type VI.

• Immediate type reaction (type I): The binding of a drug to IgE antibodies leads to the release of mediators of an anaphylactic reaction (IgE-mediated mast cell activation). Clinically, urticaria, angioedema, dyspnoea or cardiovascular problems occur. These IgE-mediated drug reactions occur mainly with antibiotics, insulin or muscle relaxants. In question is an IgG-mediated immediate drug reaction by binding of the antibodies to basophilic or neutrophil granulocytes and consecutive release of mediators. Note: Certain drugs such as opiates, muscle relaxants, x-ray contrast media, various other drugs may be used. Biologics can induce direct histamine liberation and thus cause urticarial exanthema. Non-steroidal anti-inflammatory drugs can cause an increased release of leukotrienes in the context of analgesic hypersensitivity.
• Humoral cytotoxic reactions (type II): Drugs can form "neo-antigens" through non-specific adherence to cells or through interactions with the cell membrane, which are fixed by IgG antibodies, or more rarely by IgM antibodies. Furthermore, soluble drugs can form immune complexes with IgG or IgM antibodies, which are then bound to cells via Fc receptors and consecutively activate complement. Cytotoxic reactions mainly affect cells of the hematopoietic system: anemia due to cephalosporins, granulocytopenia and thrombocytopenic purpura due to sulfonamides and heparin. The sensitization phase with formation of appropriate antibodies takes about 5-10 days. The effector phase until the onset of clinical symptoms lasts 2-3 days.
• Immune complex reaction (type III): This reaction is initiated by aggregates of drug haptens + carrier protein which in this constellation induce antibodies or immune complexes (sensitization phase lasts about 10 days). These consist exclusively of drug-specific immunoglobulins (mostly IgG, IgM or, as in the case of Purpura Schönlein-Henoch, IgA). These circulating immune complexes can precipitate in postcapillary venules and induce leukocytoclastic vasculitis. Sometimes an immune complex reaction can be exaggerated by an excessive activation of the complement system (clinical: serum disease).
• T-cellular reactions (type IVa-d): The sensitization process generates drug-specific inflammatory and cytotoxic T-lymphocytes. Depending on the lymphocyte population involved, an immunological subdivision into forms IV a-d is postulated. However, no independent clinical pictures can be assigned to forms IV a-c (immune type IV d plays a role in generalized exanthematic pustulosis).
  • Type IVa: formation of INF-gamma or TNF-alpha secreting CD4+T lymphocytes.
  • Type IVb: formation of IL-5/IL-4/IL-13 secreting CD4+T lymphocytes (Th2 lymphocytes)
  • Type IVc: Formation of perforin- and granzyme B-producing CD8+ and CD4+ T-lymphocytes (cytotoxic T-lymphocytes). The release of these cytokines causes reversible keratinocyte damage to the skin with vacuolisation and dyskeratosis or cell necrosis and blistering(erythema multiforme, fixed drug reaction).
  • Type IVd: Formation of CXCL8 - and GM-CSF-secreting T cells. These cytokines are mainly responsible for the recruitment of neutrophilic granulocytes. The reaction type IVd plays a role in the development of acute generalized exanthematic pustulose (AGEP).
• Type V (granulomatous reactions): This reaction type concerns cellular reactions involving monocytes and Th1 lymphocytes. These include clinical vaccine granulomas on vaccinations or allergen extracts.
• Type VI (immunodeviations): In this type of reaction, drugs induce autoantibodies or suppression of regulatory T cells, inflammatory or autoimmunological immune reactions by stimulating inflammatory T cell populations. Triggers are mainly so-called biologicals such as TNF-alpha-antagonists or checkpoint inhibitors (see below biologicals). Clinical examples are autoimmune phenomena during treatment with CTLA-4 or PD1 antibodies in tumor patients. Paradoxical reactions during the therapy of psoriasis with TNF-alpha-blockers are also attributed to this type of reaction.

In "non-immunological drug hypersensitivity" an immunological - allergic - mechanism is not detectable: