Fever, rash, and systemic symptoms: understanding the role of virus and HLA in severe cutaneous drug allergy

Abstract

Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell-mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design.

Keywords: ABC; ADR; AGEP; Abacavir; Acute generalized exanthematous pustulosis; Adverse drug reaction; CBZ; CMV; CTL; Carbamazepine; Cytomegalovirus; Cytotoxic lymphocyte; DIHS; DRESS; DRESS-DIHS-HSS; Drug reaction with eosinophilia and systemic symptoms; Drug-induced hypersensitivity syndrome; EBV; Epstein-Barr Virus; HHV; HLA; HSR; HSS; Human herpesvirus; Human leukocyte antigen; Hypersensitivity reaction; Hypersensitivity syndrome; INF-γ; Interferon gamma; NSAID; Nonsteroidal anti-inflammatory drug; Orally; PBMC; Peripheral blood mononuclear cell; SCAR; SJS; SJS-TEN; Severe cutaneous adverse drug reaction; Steven-Johnson syndrome; T-cell receptor; TCR; TEN; Toxic epidermal necrolysis; Twice a day; Viral reactivation; bid; po.

Figure 1

(A) Clincial timeline for the development of Carbamazepine associated TEN in the case study patient. (B) Negative petrolatum control and positive patch test for 0.1%-10% carbamazepine in the patient 9.5 years after the original TEN reaction (left) and positive PBMC INF-g Elispot for 5-10ug/mL carbamazepine for 100 000 cells/well for a sample taken 17 years after the clinical TEN reaction (right). Positive controls (CD3+ and CEF peptide pool) and unstimulated PBMCs are also shown.

Figure 1

(A) Clincial timeline for the development of Carbamazepine associated TEN in the case study patient. (B) Negative petrolatum control and positive patch test for 0.1%-10% carbamazepine in the patient 9.5 years after the original TEN reaction (left) and positive PBMC INF-g Elispot for 5-10ug/mL carbamazepine for 100 000 cells/well for a sample taken 17 years after the clinical TEN reaction (right). Positive controls (CD3+ and CEF peptide pool) and unstimulated PBMCs are also shown.

Figure 2

Geographical distribution and frequency of the key drug HSR alleles associated with abacavir HSR, allopurinol DRESS/DIHS/HSS and SJS/TEN and carbamazepine SJS/TEN HLA-B*57:01, HLA-B*58:01 and HLA-B*1502, respectively. Red = HLA-B*57:01 frequency, Blue = HLA-B*58:01 frequency and Green = HLA-B*15:02 frequency.

Figure 3. The Abacavir-HLA-B*5701 Clinical Roadmap

The abacavir-HLA-B*5701 example illustrates the necessary steps required to move from identification of the HSR and risk alleles to implementation of clinical screening prior to administration of the drug.