Drug Hypersensitivity

Abstract

Background: Adverse drug reactions (ADRs) can be divided into pharmacological ADRs (type A) and hypersensitivity reactions (type B). Type B reactions can be further subdivided into immediate (<1 h, urticaria, anaphylaxis) and delayed reactions (>1 h, variable manifestation like exanthema, hepatitis, cytopenias). Prevention of hypersensitivity is often still a challenge.

Methods: Selective literature search in Medline and Google Scholar as well as research in ADR databases like OpenVigil or SIDER.

Results: Laboratory tests ([specific] IgE, lymphocyte transformation test), histological examination, dermatological tests (prick tests, epicutaneous testing) and-under certain circumstances-provocation tests can be used for diagnostics. There are only a few pharmacogenetic biomarkers to predict hypersensitivity reactions. Currently, testing for defined HLA genes is mandatory before prescription of abacavir and before the use of carbamazepine in Han Chinese or Thai patients. Immediate discontinuation of the trigger is essential in all allergic hypersensitivity reactions. Immediate reactions are treated with antihistamines, glucocorticoids and occasionally with epinephrine. Delayed reactions are usually treated with glucocorticoids.

Conclusion: Careful, structured diagnostics in case of suspected hypersensitivity together with adequate documentation (allergy passport) is necessary in order to avoid incidents in patients receiving subsequent treatment. Consistent use of existing resources (diagnostics and documentation) can help to avoid hypersensitivity reactions or to rapidly recognize and treat them, respectively.

Figure 1

Hypersensitivity reactions with their immunological classification, classical clinical entities, and examples of precipitating drugs (in red). AGEP: acute generalized exanthematous pustulosis, AP: alkaline phosphatase, ASAT: aspartate aminotransferase, DIA: drug-induced agranulocytosis, DILI: drug-induced liver injury, DIRI: drug-induced renal injury, DRESS: drug reaction with eosinophilia and systemic symptoms, GFR: glomerular filtration rate, IgE: immunglobulin E, IgG: immunglobulin G, IgM:immunglobulin M, MPR: maculopapular rash, NSAID: nonsteroidal anti-inflammatory drugs, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis.

Figure 2

Cutaneous manifestations of type IV hypersensitivity reactions, in order of increasing mortality: A) maculopapular rash (MPR): macule and several papules, markedly confluent, without any further systemic manifestations B) drug reaction with eosinophilia and systemic symptoms (DRESS): variable clinical picture, predominantly papules over the entire body, systemic manifestations including eosinophilia and fever C) Stevens-Johnson syndrome (SJS): blisters and epidermal separation (erosions) that typically start on the face and are later seen mainly on the trunk D) Reactions with skin separation over larger areas are designated as toxic epidermal necrolysis (TEN) or Lyell syndrome. E) Urticaria in a type I reaction for comparison: hives (wide area,raised), pruritus F) Oral mucosal involvement in erythema exsudativum multiforme (Fuchs syndrome) for comparison: less mucosal involvement than in SJS, skin lesions often slightly raised.

eFigure

Mechanisms of organ damage (after [e27]). Drugs can induce adverse drug reactions (ADR) in a variety of ways. For example, liver damage can be caused directly by the oxidation of hepatic proteins by the toxic acetaminophen metabolite N-acetyl-p-benzoquinonimine (NAPQI) (type A ADR). The extent of NAPQI production depends mainly on clinical factors. Cell death secondarily activates the immune system. Diclofenac, togther with hepatic proteins, can form haptens that are recognized by antibodies (type B ADR). There is subsequent cell destruction, with an immune reaction. Finally, some drugs can also directly activate T-cell receptors or killer-cell-immunoglobulin-like receptors (the so-called PI concept, i.e., the pharmacological interaction of drugs with immune receptors [e28]).