Comparatively rare but serious adverse reactions (SCAR) are life-threatening. The focus of this study is on non-APH phenotypes (non-IGE-mediated), with an emphasis on diagnosis and management of acute widespread eosinophilic (AGEP), eosinophilic and systemic symptoms (DRESS) drug reactions, Steven-Johnson Syndrome, and toxic epidermal necrolysis (SJS), respectively (TEN). The review examines recent guidelines on optimal supportive care, as well as papers on interventional treatment for SJS/TEN, such as various immunomodulating treatments and management options for severe ocular illness using amniotic membrane transplantation. Long-term autoimmune consequences are increasingly recognised in DRESS, and techniques for treating the acute episode are being modified. If the causative drug is not obvious from a comprehensive examination of the drug exposure history, in-vitro diagnostics, HLA testing, and skin testing may be examined before drug challenge testing, and they propose an approach for investigating complex situations.

Careful phenotypic analysis of the increasingly complex recognised SCAR patterns aids in our understanding of T-cell mediated drug hypersensitivity and allows for the improvement of in-vitro diagnostic testing to minimise patient exposure to test substances in all but a very small number of cases, thereby improving safety.