ARTICLUO EXCELENTE

1. Drug Reaction with Eosinophilia and Systemic Symptoms: an
update on pathogenesis
Xavier Camous1
, Sebastien Calbo1
, Damien Picard2
and Philippe Musette2
The syndrome termed ‘Drug Reaction with Eosinophilia and
Systemic Symptoms’ (DRESS) is an unpredictable, life-
threatening condition associated with adverse reactions to
therapy. Although the etiology of DRESS is poorly understood,
genetic susceptibility markers have been identified within the
HLA complex and there are several prevailing models of
pathogenesis. Modification of host antigens by haptens (drugs
or their metabolites), or non-covalent drug binding to
endogenous proteins (the p-i concept), may drive pro-
inflammatory immune responses in patients. Alternatively, a
viral trigger for DRESS has been proposed based on the
concomitant detection of herpesviruses and the recent
demonstration of Epstein–Barr virus-specific immune
responses in DRESS patients. In the present review, we
discuss the latest findings concerning the pathogenesis of drug
reactions and known risk factors for DRESS.
Addresses
1
Biomedical Sciences Institutes, Singapore Immunology Network
(SIgN), A*STAR, 8A Biomedical Grove #4 Immunos Building, Singapore
138648, Singapore
2
INSERM U905, Rouen University Hospital, Rouen 76000, France
Corresponding author: Musette, Philippe (philippe.musette@chu-
rouen.fr)
Current Opinion in Immunology 2012, 24:730–735
This review comes from a themed issue on Allergy and hypersensitivity
Edited by Hans-Uwe Simon and Steven F Ziegler
For a complete overview see the Issue and the Editorial
Available online 11th October 2012
0952-7915/$ – see front matter, # 2012 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.coi.2012.07.010
Introduction
Drug Reaction with Eosinophilia and Systemic Symp-
toms (DRESS) is a type of severe cutaneous drug erup-
tion (DE), being a class of adverse reactions to therapies
that also includes Steven–Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TEN). The initial
sequence of events that drives the pathogenesis of DE
may be consistent between the three different forms of
severe DE, while specific outcomes and clinical manifes-
tations are influenced by patient-intrinsic factors that
have yet to be identified. DRESS is a disease difficult
to diagnose since the symptoms mimic those of several
other pathologies and can appear a long time after initial
drug exposure. A diagnostic tool known as the RegiSCAR
criteria grid was thus created to better diagnose DRESS
in drug-treated patients [1]. RegiSCAR is based on seven
parameters and mandates three or more primary symp-
toms (fever >38 8C, acute skin rash, lymphadenopathy,
internal organ involvement, blood count abnormalities)
for a diagnosis of DRESS. An update to this approach was
subsequently developed and named the ‘Japanese con-
sensus group diagnostic criteria for DIHS’ (drug-induced
hypersensitivity syndrome) [2]. This diagnostic tool
requires that at least seven of nine patient symptoms
must be present to identify DRESS (rash development
more than three weeks after starting medication, symp-
toms not stopped by drug discontinuation, fever, liver
abnormalities, leukocyte abnormalities, leukocytosis, aty-
pical lymphocytosis, lymphadenopathy and re-activation
of human herpesvirus 6 (HHV-6). In DRESS, the liver,
kidneys and lungs are the organs most often involved in
the disease process, and the most common blood abnorm-
alities include atypical lymphocytes, eosinophilia and
lymphocytopenia. Affected patients are usually treated
with immunosuppressive drugs including corticosteroids,
and full recovery is achieved in up to 90% of cases.
Drug-specific T-cells have been identified as the primary
effectors of disease in DE patients [3]. However, T-cells
from healthy donors can also efficiently respond to drugs,
despite a lack of previous drug exposure [4–6]. These data
predict a far higher incidence of DE than observed in
human patients. DE is rather a rare disease, and factors
that effectively identify ‘at-risk’ individuals within a
population of patients receiving a given drug have yet
to be determined. While some genetic susceptibility of
DE is associated with the HLA loci [7–11], these findings
alone cannot account for DE prevalence, since the ident-
ified HLA susceptibility alleles are neither necessary nor
sufficient for disease development [12]. More recently, a
link was established between drug re-activation of
endogenous herpesvirus and presentation of DRESS in
treated patients [2]. However, there is as yet no evidence
that re-activation of dormant viruses can occur in SJS and
TEN. The present review focuses on the latest advances
in our understanding of the pathogenesis of DRESS.
The hapten theory and p-i concept
To better understand the role of HLA molecules in
severe cutaneous drug reactions, a brief description of
the hapten theory and p-i concept is necessary (Figure 1)
[3]. Haptenation is a process whereby a small and immu-
nologically neutral molecule becomes antigenic when
bound to a protein [13,14
]. Pro-hapten molecules must
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Current Opinion in Immunology 2012, 24:730–735 www.sciencedirect.com

2. first be metabolized by detoxification enzymes to become
able to bind to proteins. Since haptens cannot discrimi-
nate between individual patients, and detoxification
enzymes are expressed by all drug recipients, it has been
proposed that polymorphisms in the genes that encode
detoxification enzymes may be responsible for the de-
velopment of DRESS in only a subset of patients. How-
ever, no such polymorphism has been identified that
correlates with the occurrence of patient drug reactions
[9,15,16]. Indeed, the majority of drugs studied can be
recognized by patient T-cells despite lacking hapten-like
features [17]. Labile binding of drugs or their metabolites
to MHC molecules that induce T-cell responses has been
termed the ‘p-i’ concept (pharmacological interaction of
drugs with immune receptor) [18]. The fact remains that
T-cells in healthy donors have the capacity to be stimu-
lated by drugs just as potently as T-cells in patients,
thereby indicating the involvement of additional
susceptibility factors [4–6].
Drug interactions with HLA type
In the hapten-driven and p-i models of DRESS patho-
genesis, drugs or their metabolites bind to host proteins to
induce immune responses. Assuming that the protein
involved is not unique to affected patients, these models
predict that any treated individual may be at risk of
DRESS whenever a new medication is administered.
However, very promising results have been obtained
indicating that specific HLA variants may be partially
responsible for increased risk of DRESS. The first study
to describe a relationship between drug susceptibility and
HLA type was conducted by Mallal et al. in 2002 [8], and
identified a link between HLA type in HIV-positive
Caucasians and development of hypersensitivity to aba-
cavir (a nucleotide analog that acts as a HIV reverse
transcriptase inhibitor). Mallal and colleagues showed
that expression of HLA-B*5701 was strongly associated
( p 0.0001) with abacavir hypersensitivity. The mech-
anism of T-cell activation by abacavir was subsequently
elucidated by Illing et al. in 2012 [19
], and confirmed by
other investigators [20,21]; abacavir is able to bind non-
covalently to the peptide-binding groove of the HLA-
B*5701 molecule (but not to the related HLA-B*5703)
and thereby induces a T-cell response against the modi-
fied MHC/self peptide complex. This modification of
endogenous proteins effectively renders the involved
tissues ‘allogeneic’, which may explain the particular
magnitude of the inflammatory response induced. Impor-
tantly, the authors also showed that non-covalent drug
binding in the MHC groove altered the self-peptide
repertoire, thus also providing a possible explanation
for cases of autoimmunity that can occur following DE
DRESS Camous et al. 731
Figure 1
T cell
TCR
Peptide
Drug
HLA
(I or II)
APC
A B C
IMMUNE RESPONSE
Current Opinion in Immunology
Models of drug-specific T-cell activation. Drugs can bind covalently to the MHC (a) and to peptides (b), or can become non-covalently embedded
within the MHC groove. Drug binding may expose peptide residues not usually displayed for TCR binding, or could perhaps modify the repertoire of
peptides presented by a given MHC molecule. If the drug-modified structure is subsequently recognized by a T-cell in the context of co-stimulation, T-
cell responses will then be initiated.
www.sciencedirect.com Current Opinion in Immunology 2012, 24:730–735

3. [22,23]. However, we know that not all HLA-B*5701
positive patients will develop a DE in response to aba-
cavir [12], suggesting other risk factors.
Carbamazepine is an anti-convulsant drug and well-estab-
lished inducer of hypersensitivity reactions. Suscepti-
bility to carbamazepine has been linked to patients
that carry the HLA-B*1502 variant [9]. The proposed
mechanism of T-cell activation by carbamazepine is
similar to that described above for abacavir [19
].
HLA-B*1502 is very commonly expressed in South East
Asia population and is almost exclusive of this region. In
contrast, carbamazepine responses in Europeans descent
are associated with the expression of HLA-B*3101 [11].
Similarly, gout medication allopurinol is known to induce
reactions in HLA-B*5801 carriers [10]. All of these associ-
ations are likely to share a comparable mechanism of
patient T-cell activation that depends on drug modu-
lation of the host MHC/peptide repertoire, although
rigorous proof of this mechanism is currently lacking.
The identification of DE risk-associated HLA variants
has opened new doors for healthcare practitioners by
enabling patient stratification for DE susceptibility using
simple HLA typing techniques. A Taiwanese study of
almost 5000 patients categorized their cohort according to
HLA haplotype [24
], and administered a substitute for
carbamazepine in patients carrying the HLA-B*1502
variant. By conducting HLA typing before drug prescrip-
tion, the incidence of drug disorders was dramatically
reduced, and none of the patients developed either SJS or
TEN (despite a predicted incidence of 0.23%, equivalent
to 10 cases of SJS or TEN among the 4120 study subjects
who took carbamazepine). Mild rash was observed in only
6% of non-HLA-B*1502 patients, and 0.1% of these
patients required hospitalization, implicating additional
risk factors for drug reactions in this population. Screen-
ing patients’ HLA haplotype before administering medi-
cations could therefore be a very efficient method of
reducing the number of severe drug reactions. For a
complete review of HLA associations with drug hyper-
sensitivities, please refer to Bharadwaj et al. [25].
Anti-viral responses
The observation that DRESS can re-activate dormant
viruses in affected patients, especially in individuals
infected with members of the human herpesviridae
family [26–29], has led to the hypothesis that viruses
may play a key role in DRESS pathogenesis. The first
virus shown to be re-activated in DRESS patients was
human HHV-6 [30]. This double-stranded DNA virus,
first discovered in 1986 [31], infects most humans in the
first year of life and induces roseola infantum, a disease
associated with fever and skin rash. HHV-6 involvement
has been reported in a large number of different pathol-
ogies including AIDS [32], multiple sclerosis [33], chronic
fatigue syndrome [34], graft complications [35], epilepsy
[36] and cancers [37]. The main feature of HHV-6 is the
virus’ capacity to infect T-cells [31] and to dysregulate
CD8+
lymphocytes by inducing ectopic expression of
CD4 [38]. In 2010, Marviridin et al., by showing that
HHV-6 replication can be induced in vitro by amoxillicin,
hypothesized that this antibiotic induces DRESS by
promoting viral reactivation [39]. Now, it has been estab-
lished that nearly every member of the herpesviridae
family can be re-activated by DRESS-inductive medi-
cation, including Epstein–Barr Virus [28], Cytomegalo-
virus [40], Varicella Zoster Virus [41] and HHV-7 [27]. We
demonstrated that a massive, system-wide, anti-viral T-
cell response is ongoing in DRESS patients [42
]. In this
study of 40 cases of DRESS, we showed that EBV-
specific CD8+
T-cells were substantially over-
represented within the T-cell pool, comprising up to
21% of total cytotoxic T-cells in DRESS patients com-
pared with 0.1% in control patients. Activated T-cells
were producing large quantities of TNFa, IL-2 and
IFNg, which are key mediators of the ‘cytokine storm’
that can promote the characteristic symptoms of DRESS
syndrome (Figure 2). Moreover, EBV-specific T-cells
were also detected in the liver, skin and lungs, which
are the most commonly affected organs in DRESS
patients. Interestingly, we also showed that the culprit
drug was able to promote viral reactivation [42]. In this
respect, re-activation of herpesvirus followed by broad,
uncontrolled anti-viral T-cell responses that lead to a
state of generalized inflammation (with associated organ
failure), may be a unique feature of DRESS. Indeed,
evidence of herpesvirus re-activation during SJS and
TEN is still a matter of debate [43,44]. Further investi-
gation will now be required to elucidate the nature of the
drug-specific T-cell response in DRESS patients, and to
better understand the influence of drugs on the course of
human anti-viral immune responses. Intriguingly, since
DRESS induces inflammation, this syndrome can also
promote the expansion of regulatory T-cell populations
(T-reg) [45] that are susceptible to infection by viruses
such as HHV-6 [46]. Altered function of virus-infected T-
reg may therefore contribute to the dysregulated immune
response observed in DRESS.
Toward a unified theory of DRESS
pathogenesis?
Sulfamethoxazole (SMX) is an antibiotic which can be
processed into the metabolite N-acetyl-SMX by the
enzymes cytochrome P450 [47] and myeloperoxidase
[48] in detoxification organs. While the bulk of N-
acetyl-SMX is excreted in urine, a small part is further
metabolized into SMX-hydroxylamine (SMX-HA) which
can autoxidize to form SMX-NO and stimulate immune
cells [49]. In 2009, a study from Lavergne et al. showed
that ‘danger signals’ can lead to an increase in protein-
SMX adducts in peripheral blood mononuclear cells and
dendritic cells [50], revealing an alternative route by
which DRESS could be induced in drug-treated patients.
Under these conditions, SMX-NO binds preferentially to
732 Allergy and hypersensitivity
Current Opinion in Immunology 2012, 24:730–735 www.sciencedirect.com

4. cysteine residues, and Callan et al. showed that optimal
binding was obtained when those amino acids were oxi-
dized as sulfenic acids [51]. Several factors have been
shown to modify cysteine oxidation levels, including oxi-
dative stress and various pathological conditions [50,52,53].
By mimicking several pathogenic conditions in turn (using
lipopolysaccharides, staphylococcal enterotoxin B, and
inactivated H2N2 flu virus), Lavergne et al. showed that
key cytokines involved in the induction of immunological
stress (IL-1b, IL-6, IFN-g, TNF-a) or mediators of inflam-
mation and hyperthermia (prostaglandin E2, activated
protein C and human serum complement) promote
accumulation of oxidized cysteines and thus an increase
in adduct formation. In vivo, ‘danger’ signals such as these
may well be expressed following the re-activation of
endogenous viruses, leading to increased cysteine oxi-
dation and accompanying adduct formation. This
sequence of events could also explain why HIV patients
receiving tritherapy are particularly susceptible to devel-
opment of DE, since ongoing inflammation in these
patients coupled with the daily administration of drugs
may facilitate adduct formation. It is thus increasingly clear
that the hapten model, p-i concept and viral hypothesis can
be unified into a single model of DE pathogenesis that is
critically influenced by patient HLA type.
Conclusion
Despite considerable advances in our understanding of the
mechanisms that promote DRESS, many unanswered
questions remain regarding the pathogenesis of this syn-
drome. Critically, the relative scarcity of DRESS cannot be
explained by existing data. Virtually all human adults have
been infected by several herpesviruses, and all HLA hap-
lotypes are capable of binding to drug metabolites and
haptenated peptides. We hypothesize that the location and
orientation of hapten binding is an important determinant
of DRESS susceptibility, or alternatively, that only rare
drug-modified peptides are capable of eliciting a T-cell
response. In addition, future studies will need to evaluate
DRESS Camous et al. 733
Figure 2
CLA4+
CCR4
CCR10
Cutaneous eruption
Antiviral response
B cell
HLA-I
EBV-specific
CD8 T cells
IFNγ
TNFα
Drug
T cell
TCR
Virus
production
Systemic
effects
Antidrug response
T cell
Naïve B cells Dendritic cells Monocytes Keratinocytes
EBV virus
Current Opinion in Immunology
DRESS pathogenesis. In this model, drugs re-activate EBV within the B cell reservoir. Virus re-activation increases MHC presentation of virus peptides
to EBV-specific memory T-cells, which provides the necessary co-stimulation for activation of drug-specific T-cells by the same antigen presenting
cell. Cytolysis then releases new virions to infect nearby host cells and further stimulate EBV-specific T-cell responses, thereby establishing a pro-
inflammatory environment which supports the activation of additional drug-specific T-cell clones. This sequence of events will gradually generate a
‘cytokine storm’ which leads to the systemic effects observed in DRESS patients.
www.sciencedirect.com Current Opinion in Immunology 2012, 24:730–735

5. the influence of drug metabolites and drug-specific T-cells
responses on anti-viral immunity in treated patients.
Acknowledgement
We thank Neil McCarthy of Insight Editing London for proof-reading the
manuscript.
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