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.