II) Viraemia after DRESS: induced replication or mostly release of endogenous viruses?
It is still a matter of debate whether viraemia of herpes viruses is a causative or reactive factor in DRESS and to which extent the viraemia is clinically relevant.
In the Japanese definition of DRESS/DiHS, herpes virus infection (mainly CMV) is considered an important cause of DRESS morbidity and mortality and HHV6 viraemia even figures as a diagnostic criterium [54].Consequently, they recommend antiviral therapy in DRESS/DiHS [69].
The virus-release hypothesis, presented here, sees viraemia as a secondary phenomenon. Viraemia in this case would not precede, or even induce, the drug-directed T cell response. The virus-release hypothesis is compatible with the potential simultaneous increase of various herpes viruses (HHV6, CMV, EBV) in the blood [59]. Since most patients do not exhibit viraemia-associated symptoms, antiviral treatment in these asymptomatic patients would not be warranted. Indeed, antivirals and other new medications should be avoided in DRESS patients since they tend to develop “multiple drug hypersensitivity” [70][71]. However, multiple drug hypersensitivity symptoms due to antiviral medication have not been reported in Japan.
In summary, viral infections might prime the immune system for DHR by enhancing immune reactivity to drugs (p-i) and hapten-protein complexes. Consequently, severe DHR may cause viral particle release/viraemia due to the actions of cytotoxic T cells. However, these conclusions are still hypothetical and need further substantiation. In particular, we need more clinical and immunological data on the type and duration of drug-induced immune reactions. However, such data are difficult to obtain with an iatrogenic disease like DHR and even more difficult to obtain for a combination of viral infection and DHR.
Nevertheless, one should start with a more precise clinical evaluation of DHR. We should aim at substituting the term ”rash” with a more exact description of the exanthema, especially the extent and severity of the reaction and its duration – a picture is always helpful. Furthermore, signs of even mild systemic involvement/severity, as evidenced by eosinophilia, lymphocytosis and elevation of liver enzymes, should be more carefully considered in DHR. We should not forget that it is an iatrogenic disease, which needs particular attention. Such a more in-depth approach and the resulting data may help us further dissect and understand DHR in viral infections. In consequence, this may help to avoid the obvious mislabelling of often very young patients with mostly harmless, transient exanthema as permanently penicillin-allergic, which may cause much confusion in daily clinical practice. Finally, the question arises if one should not consider virus-enhanced reactions in the risk assessment of certain drugs-like antibiotics.
Authorship statement: W.J.P. developed the concepts and formulated them. M.-C.B. contributed to the concept, drafted and edited the manuscript.
Conflict of interest statement: WJP has received consulting fees (all to ADR-AC) by Roche, argenix, Staten. Sotck or stock options for Novartis, Bioncore, Roche. MCB has received grants and research funding from the Swiss National Science foundation (SNF), Christine Kühne Center for Allergy Research and Education (CK-CARE), Freenovation foundation, LEO foundation, Olga Mayenfisch foundation, the University of Zurich, LEO Pharma, the Eczema Foundation of Pierre Farbre, SwissLife foundation, Vontobel foundation, EMDO foundation. Speaking and/or consultation fees from Eli Lilly, LEO Pharma, AbbVie, and AstraZeneca. Speaking honoraria / presentations, educational events: CK-CARE, University Hospital Basel, FOMF, ADR-AC, SGAI.