Drug hypersensitivity: Mechanisms and opportunities of laboratory diagnostics

Abstract

Permanently increased frequency of drug hypersensitivity is observed throughout the world and continues to be of concern to clinicians of either discipline. Diagnostic problems with prevention and treatment of hypersensitivity reactions are due to different pathogenetic mechanisms that may underly similar clinical manifestations. On the other hand, clinical symptoms, response to therapy and the outcome of the disease significantly depend on clinical state of the patient. The phenotypes which are determined by clinical manifestations, and endotypes dependent on the pathogenetic mechanisms of hypersensitivity reactions were specified to the purpose of personalized therapy. Two kinds of phenotypes are described: with immediate (1-6 hours) and delayed (more than 6 hours) onset of the response. Four types of hypersensitivity according to Gell and Coombs with the presence of primary sensitization are discerned between the endotypes. Moreover, interaction of drugs with immune receptors of lymphocytes, according to the Pichler’s pharmaco-immune concept, has been identified, along with quick impact of drugs directly upon receptors of effector cells and signaling cascades without primary sensitization, which was previously termed as “pseudo-allergy”. To optimize therapy and prevent repeated reactions in the patients with drug hypersensitivity, high-quality diagnostics with detection of the causal allergen is required. This strategy currently includes analysis of medical history, physical examination as well as in vivo and in vitro testing. Provocation tests are rarely used, due to the significant risk of severe adverse reactions. Skin tests are a reliable and cost-effective tool, if the case history infers possibility of IgE-dependent reactions. Among nonspecific laboratory markers, the greatest clinical value is shown for determining serum tryptase levels, especially in anaphylactic reactions. In addition to genetic testing, several specific laboratory methods are used, i.e., measuring levels of drug-specific IgE, assessment of antigen-induced activation and proliferation of lymphocytes as well as basophil activation test, which has a number of advantages and allows us to identify a causally significant allergen for the hypersensitivity reactions proceeding by various mechanisms. Due to dysregulation which is a key factor of allergic inflammation, the mechanisms of normalization for impaired immune regulation should be understood, thus offering new strategies for personalized treatment, e.c., modulating the regulatory cell functions, aiming for control of the drug hypersensitivity reactions.