Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America

Abstract

Drug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. perspectives. While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated.

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

“…The classification of HSRs relies on the clinical presentation of typical symptoms and their timing [2,7], and were originally described by Gell and Coombs [8]: namely Type I (IgE mediated reactions), Type II (antibody mediated cytotoxicity reactions), Type III (immune complex-mediated reactions), and Type IV for delayed type hypersensitivity. Recently phenotypes, endotypes, and genotypes for these HSRs are being elucidated and applied to provide personalized approaches to treating and managing HSRs (Figure 1) [1].…”

“…More severe reactions with vital sign changes, throat tightness, or swelling can also appear [1,2,7,15]. Previous sensitization to the drug is usually required but cross reactivity has been described between drugs and other allergens (for example in pollen allergic patients who develop taxane hypersensitivity) [9].…”

“…These phenotypes and endotypes can be further assessed through biomarkers such as skin testing (ST), and specific IgE and basophil activation tests (BAT), which help identify mast cell involvement in the HSRs as well as cross reactivity between drugs [7,9,10,11,25,26,27,28,29]. Levels of basophil/mast cell activation mediators during HSRs, such as tryptase and histamine, or cytokine and leukotriene production, may be helpful in identifying cells involved in the HSR.…”

“…Levels of basophil/mast cell activation mediators during HSRs, such as tryptase and histamine, or cytokine and leukotriene production, may be helpful in identifying cells involved in the HSR. These mediators can also been usedin risk stratifying the patient [4,7,9,20,27,30,31]. In the last few years the relevance of genotypes in drug allergy has increased significantly; for example, specific HLA alleles have been associated with the development of hypersensitivity reactions to antibiotics, retrovirals, and anticonvulsant drugs [13,32].…”

“…HIV positive patients who present with delayed maculopapular exanthem have also been successfully desensitized, however protocols for delayed reactions have not yet been standardized [40]. DS is contraindicated in immune thrombocytopenia, serum sickness-like reactions, or SCAR (Severe Cutaneous Adverse Reactions) due to high toxicity [7,38,42]. Comorbidities, current prescriptions, and premedications should be evaluated to understand the initial reaction and appropriately risk stratify the patients because some medications may change the risk of reaction, treatment plan, or mask the severity of the initial symptoms.…”