Supplementary Material for: Multiple Drug Hypersensitivity

Multiple drug hypersensitivity (MDH) is a syndrome that develops as a
consequence of massive T-cell stimulations and is characterized by
long-lasting drug hypersensitivity reactions (DHR) to different drugs.
The initial symptoms are mostly severe exanthems or drug rash with
eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to
another drug often appear in the following weeks, overlapping with the
first DHR, or months to years later after resolution of the initial
presentation. The second DHR includes exanthema, erythroderma, DRESS,
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN),
hepatitis, and agranulocytosis. The eliciting drugs can be identified by
positive skin or in vitro tests. The drugs involved in starting the MDH
are the same as for DRESS, and they are usually given in rather high
doses. Fixed drug combination therapies like
sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently
involved in MDH, and 30-40% of patients with severe DHR to combination
therapy show T-cell reactions to both components. The drug-induced
T-cell stimulation appears to be due to the p-i mechanism. Importantly, a
permanent T-cell activation characterized by PD-1+/CD38+ expression on
CD4+/CD25low T cells can be found in the circulation of
patients with MDH for many years. In conclusion, MDH is a drug-elicited
syndrome characterized by a long-lasting hyperresponsiveness to
multiple, structurally unrelated drugs with clinically diverse symptoms.