The role of drug, dose, and the tolerance/intolerance of new drugs in multiple drug hypersensitivity syndrome

Abstract

Background Multiple drug hypersensitivity syndrome (MDH) is used to describe persons with a drug hypersensitivity reaction (DHR) to at least two chemically unrelated drugs, confirmed by skin test or in vitro assay. Methods Medical records of 25 patients with MDH, tested and confirmed at our allergy division, were retrospectively evaluated in terms of clinical course, involved drugs, daily drug dose, latency periods, test results of skin test and cellular assays, and tolerated drugs in subsequent pharmacological treatments. Results Multiple drug hypersensitivity syndrome almost exclusively appeared as a delayed, often severe DHR and started in 14/25 with a drug reaction with eosinophilia and systemic symptoms (DRESS). Penicillins (13/25, 52.0%) and cephalosporins (6/25, 24.0%), typical high‐dose drugs, were most often identified as elicitors of MDH, especially at the first DHR, followed by aromatic antiepileptics (7/25, 28.0%), vancomycin (4/25, 16.0%), and antibiotic sulfonamides (4/25, 16.0%). Cephalosporins, clindamycin, and radio contrast media (RCM) were mainly involved in subsequent DHR. The median daily drug dose of all drug trigger was 1875.0 mg (662.5; 2100.0) at the first DHR and 600.0 mg (300.0; 1300.0) at subsequent DHR, P = .0420. Conclusion High‐dose drugs, especially beta‐lactam antibiotics, RCM and clindamycin, are common elicitors of subsequent DHR in patients with MDH. Macrolides, quinolones, doxycycline, nonaromatic antiepileptics, and paracetamol were often tolerated. As the same drugs elicited both flare‐up reactions and real DHR, drug‐induced flare‐up reactions may be precursors of a possible second DHR and MDH. The administration of highly dosed drugs should be avoided in patients at risk for MDH.

Drug-related relapses in drug reaction with eosinophilia and systemic symptoms (DRESS)

“…A causative drug inducing DRESS was identified in 38 patients (82.6%) (group 2) including 13 cases with DRESS/MDH (13/46, 28.1%). These 13 patients had been described earlier [14 ]. Of the 38 cases with proven sensitization, nine and five were evaluated only by skin test and LTT, respectively.…”

“…Usually, high doses of penicillins are administered (up to 13.5 g/d! ), which may promote the development of DHR and relapses [14, 15 ]. Interestingly, the administration of betalactam antibiotics was associated with a relatively short latency (of < 10 days), an observation that was already described previously [6, 24 ].…”

“…MDH was defined as an immune mediated DHR to two or more unrelated drugs confirmed either by skin or by in‐vitro tests [14, 15 ]. A relapse was defined as a transient re‐occurrence of clinical symptoms and/or laboratory signs during or following the initial DHR (such as exanthema, recurrent eosinophilia, elevation of liver enzymes).…”

“…Relapses manifesting as exacerbations of exanthema, recurrent eosinophilia, or hepatitis are typical, even if the inducing drug is discontinued [4, 9 ]. Relapses may be related either to viral reactivations [7, 10 ], or to rapid reduction of systemic steroids [4, 11 ], or to administration of new drugs or to previously tolerated drugs after dose increase [4, 12–14 ].…”

“…In these cases patients may tolerate the suspected drug after complete recovery from the relapse. On the other hand, some patients showed a new T cell sensitization to the causing drug, leading to a multiple drug hypersensitivity syndrome (MDH) [14–16 ]. These patients are at risk of developing a drug hypersensitivity on re‐exposure [17 ], therefore, they have to avoid multiple structurally different drugs.…”