American Journal of Clinical Dermatology

https://doi.org/10.1007/s40257-018-00416-4

REVIEW ARTICLE

Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS):

How Far Have We Come?
Sylvia Aide Martínez-Cabriales1,2,3 · Fabian Rodríguez-Bolaños1,3 · Neil H. Shear1,3

© Springer Nature Switzerland AG 2019

Abstract
Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome
(DiHS), is an uncommon severe adverse reaction to medications. It is important to recognize it as it is potentially fatal and can
cause significant morbidity. From the first reports of drug reactions related to certain anticonvulsants characterized by fever,
liver enzyme elevation, and skin changes, our continuously growing understanding of this entity has allowed us to describe
its physiopathology and clinical features even further. The relationship of genetic factors, viral activation, and specific drug
exposure is now known to play a role in this disease. There is still not a widely accepted marker for DReSS/DiHS, but the
spectrum of clinical and laboratory features has now been better outlined. The mainstay of treatment is the use of systemic
corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and
cyclophosphamide have been described. We present a comprehensive review of the literature on DReSS/DiHS, focusing on
its history, etiopathogenesis, diagnosis, therapeutic approach, and outcome.

Key Points 1 Introduction

Drug reaction with eosinophilia and systemic symp-
toms (DReSS)/drug-induced hypersensitivity syndrome
(DiHS) is a severe adverse drug reaction with multi-
organ involvement that is potentially fatal; therefore, a
prompt diagnosis is critical to provide the appropriate
supportive measures and care.
It is important to counsel patients about potential cross-
reactivity with other drugs and the genetic risks in rela-
tives.
Fabian Rodríguez-Bolaños and Sylvia Martínez-Cabriales
contributed equally in the preparation of this manuscript.
* Neil H. Shear
neil.shear@sunnybrook.ca
1
Department of Dermatology, University of Toronto, Toronto,
Canada
2 We use the acronym DReSS, with a lower-case ‘e’ representing
Department of Dermatology, Autonomous University
of Nuevo Leon, Monterrey, Mexico
3
Dermatology Division, Sunnybrook Health Sciences Centre,
Toronto, Canada
“Let us hope that the day will not be far distant when we,
as physicians, will no longer earn scorn as people who pour
drugs about which we know little into patients about whom
we know less” [1]. Those were the words written by Dr. P.
Newbold in 1970 when reviewing drug eruptions. Almost
50 years later, we have come to a better understanding of the
mechanistic and clinical events during and after drug reac-
tions. This has allowed us to elucidate certain steps in their
physiopathology, propose a better classification, and, thus,
ideally provide enhanced care and treatment.
The first challenge for clinicians and researchers dealing
with severe cutaneous adverse reactions (SCARs) to drugs
is to classify them. The history of what we now call drug
reaction with eosinophilia and systemic symptoms (DReSS1)
or drug-induced hypersensitivity syndrome (DiHS) started
in the 1940s when skin reactions were initially named after
the culprit agent or their resemblance to other diseases, as
was the case for sensitivity to phenytoin (Dilantin®, then
called diphenylhydantoin), early sulfonamides, allopurinol,
1
eosinophilia. The lower case helps enforce the need to look for hema-
tologic changes such as eosinophilia as well as atypical lymphocyto-
sis, and to make it clear that eosinophilia is not necessary to diagnose
DReSS as a syndrome.

Vol.:(0123456789)

and phenobarbital. A similar situation occurred with pseu-
dolymphoma associated with carbamazepine, Kawasaki-like
disease caused by carbamazepine, and periarteriitis nodosa
associated with sulfadiazine [2–10].
In 1981, Spielberg et al. [11] reported three cases of
“phenytoin hepatitis”. Shear joined this group and recog-
nized that each of these patients had a systemic syndrome
with fever, rash, eosinophilia, liver involvement, and cervi-
cal adenopathy related to phenytoin use [11]. John Stan-
ley and Fallon-Pellicci [12] had earlier reported what was
called phenytoin hypersensitivity syndrome. Trying to
understand the complex pathogenesis of this idiosyncratic
drug reaction, Shear and Spielberg [13] performed in vitro
lymphocyte assays of the patients, concluding that reac-
tive metabolites may be involved in this hypersensitivity
drug reaction and that there was a genetic risk. This led to
recognition that more antiepileptic therapies can cause the
same systemic syndrome and that there was a high risk of
cross-reactivity among the most commonly used antiepilep-
tic drugs [13]. Furthermore, in 1985, Shear and Spielberg
[14, 15] demonstrated the in vitro production of potentially
toxic metabolites of sulfadiazine, and suggested that these
could act as haptens, causing a hypersensitivity syndrome.
Thus, in 1988, anticonvulsant hypersensitivity syndrome
was defined for the first time after the study of 53 patients
with clinical hypersensitivity reactions to phenytoin, phe-
nobarbital, and carbamazepine [13]. The authors chose this
name to make it more obvious that this syndrome could be
associated with most anticonvulsants and that there was a
risk of cross-reactivity. The syndrome included the triad of
fever, skin rash, and internal organ involvement (hepatitis,
nephritis, pneumonitis, pericarditis, and myocarditis), occur-
ring with a delay of approximately 21 days after the onset of
the medication [13, 16].
In 1996, the term “drug rash with eosinophilia and sys-
temic symptoms (DReSS)” was introduced in France by
Bocquet et al. [17]. Its use was subsequently internationally
accepted, although not everywhere [17]. Shortly after, the
authors proposed to substitute reaction instead of rash for the
‘r’ because “the skin lesions are not a constant feature”, as
they explained after the term drug-induced delayed multi-
organ hypersensitivity syndrome (DIDMOHS) was proposed
by Sontheimer and Houpt [18] in 1998. Although this term
was coined in an effort to explicitly point out the delayed
multi-organ involvement, it has rarely been used. At that
time, other investigators noticed the presence of human
herpes virus (HHV)-6 in patients with DiHS [19–21]. This
observation initiated efforts into understanding the relation-
ship between the presence of the virus and drugs—efforts
that continue today. In 2006, Japanese investigators used the
term “drug-induced hypersensitivity syndrome” (DiHS), the
diagnostic criteria of which included HHV-6 reactivation
[22].
S. A. Martínez-Cabriales et al.
In comparison with Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN), which have been
identified for years in the International Classification of
Diseases–Clinical Modification (ICD-CM) diagnosis codes,
DReSS was not identified until the 11th revision of the ICD
in 2018 with the code EH65 [23]. Previously, the code most
closely related to the DReSS/DiHS definition was L27; how-
ever, it was only introduced in October 2015 [24]. This code
included “dermatitis due to chemotherapy, dermatitis due to
drug and/or medicine taken internally, drug rash, eruption
due to drug, and generalized dermatitis due to drug taken
internally” [24].
2 Literature Search Methods
A review of DReSS/DiHS cases treated with corticoster-
oids reported in the literature was carried out by searching
PubMed/MEDLINE and EMBASE between January 1990
and May 2018. Search terms were “DRESS”, “drug reac-
tion with eosinophilia and systemic symptoms”, “drug rash
with eosinophilia and systemic symptoms”, “drug hypersen-
sitivity and eosinophilia”, “drug-induced hypersensitivity
syndrome”, systemic steroid (subheadings: therapeutic use),
cyclosporine, mycophenolate mofetil, IVIG, cyclophospha-
mide, and rituximab. Publications were limited to the Eng-
lish language.
3 Epidemiology
The incidence of DReSS/DiHS has been estimated at 1
case per 10,000 exposures to selected antiepileptics [25].
Many reports generally agree that DReSS/DiHS has no age
or sex predilection [26], but there have been some reports
of certain ethnic groups presenting with a higher incidence
[27]. As previously mentioned, DReSS/DiHS can be a life-
threatening condition, with a mortality rate of approximately
10% [28]; nevertheless, a 2013 study from the RegiSCAR
(European Registry of Severe Cutaneous Adverse Reactions
(SCAR) to Drugs and Collection of Biological Samples)
study group reported a lower percentage, with two deaths
reported during the acute phase in the 117 patients diag-
nosed with probable or definite DReSS/DiHS [29]. Unfor-
tunately, even now, many cases are undiagnosed and, there-
fore, unregistered, limiting the accuracy of data.
4 Pathophysiology
The physiopathology of DReSS/DiHS is still not completely
understood; nevertheless, thanks to the efforts of multiple
researchers, light has been shone onto the mechanisms
DReSS: How Far Have We Come?

Table 1 Common culprit drugs in drug reaction with eosinophilia and systemic symptoms (DReSS)/drug-induced hypersensitivity syndrome
(DiHS)
Category Drugs

Antiepileptic drugs Carbamazepinea, lamotriginea, phenobarbitala, phenytoin, oxcarbazepinea, gabapentin, olanzapinea

Antibiotics Amoxicillin, ampicillin, azithromycin, levofloxacin, minocyclinea, piperacillin/tazobactam, vancomycina
Anti-tuberculosis agents Ethambutol, isoniazid, pyrazinamide, rifampin, streptomycina
Anti-hepatitis C virus agents Boceprevir, telaprevir
Antipyretic/analgesics [138, 170–174] Diclofenac, celecoxib, ibuprofen, aspirina
Sulfonamides Dapsone, sulfamethoxazole–trimethoprim, sulfasalazinea
Targeted anticancer agents Sorafenib, vismodegib, vemurafenib
Others Allopurinola, amitriptylinea, atorvastatina, Chinese herbal medicine, imatinib, mexiletine, omeprazole,
strontium ranelate, hydroxychloroquinea, nevirapine [175]
a
definite DReSS/DiHS cases according to the RegiSCAR scores published in the literature
Adapted from Cho et al. [30] and Cacoub et al. [46]

involved. Current evidence shows that DReSS/DiHS tends
to occur in genetically predisposed individuals when they
are exposed to certain drugs (Table 1). In addition to drug
hypersensitivity, the reactivation of HHVs and subsequent
antiviral immune responses may also contribute to a higher
severity and a more protracted course of DReSS/DiHS [30].
4.1 Genetic Factors
A genetic predisposition for cutaneous drug reactions had
been suspected for a long time, but it was in 2002 when the
first clear hypersensitivity reaction associated with specific
human leukocyte antigen (HLA) subtypes was established
[31]. These HLA subtypes have been determined for cer-
tain drugs and have been part of the means to prevent drug
reactions in certain populations. HLA-A*31:01 is linked to
DReSS/DiHS induced by carbamazepine in northern Euro-
pean, Japanese, southern Chinese, and Korean populations
[32]. In 2006, Hung et al. [33] published the association
of HLA-A*31:01 in Chinese patients. This allele was seen
in 25.8% (8/31) of those with so-called ‘maculopapular
eruption or exanthem’ (MPE)/hypersensitivity syndrome,
but only in 2.8% (4/144) of the control group (odds ratio
[OR] = 12.17, 95% confidence interval [CI] 3.6–41.2;
p = 0.0021) [33]. In 2011, Kim et al. [34] reported the pres-
ence of the HLA-A*31:01 allele in 58.8% (10/17) of carba-
mazepine-induced hypersensitivity cases and in 14% (7/50)
of the carbamazepine-tolerant controls (OR = 8.8, 95% CI
2.5–30.7; p = 0.011); this was higher than in the Korean gen-
eral population (OR = 12.4, 95% CI 4.5–34.1; p = 2.9 × 10−6)
[34]. In the same year, a Japanese study reported the pres-
ence of HLA-A*31:01 in 60.7% (37/61) of the patients with
carbamazepine-induced cutaneous adverse drug reactions,
including DiHS, showing a sensitivity of 60.7% and a spec-
ificity of 87.1% [35]. They also reported a prevalence of
2.9% of this allele in the Japanese general population, with
estimated positive and negative predictive values of 12.7%
and 98.7%, respectively. In a European study, the presence
of the HLA-A*31:01 had a sensitivity and specificity of 26%
and 96%, respectively. McCormack et al. [32] reported a
prevalence of 5% of this allele in Europeans; its presence
caused a risk of carbamazepine-induced hypersensitivity
reactions, including DReSS/DiHS, of up to 26%, and its
absence reduced the risk to 3.8%. In this study, an OR of
12.41 (95% CI 1.27–121.03; p = 0.03) was found when 26
patients with DReSS/DiHS were compared with 257 control
subjects without adverse drug reactions. In Asians, the risk
of developing carbamazepine hypersensitivity was increased
nine-fold in those who carried an HLA-A*31:01 [36]. This
allele, HLA-A*31:01, appears to be specific for carbamaze-
pine-induced cutaneous adverse drug reactions since it was
not relevant for lamotrigine- and phenytoin-induced hyper-
sensitivity reactions in Europeans [37].
Another drug that has been linked to a specific HLA
is allopurinol, especially to HLA-B*58:01, which is seen
mostly in Asian populations and some Europeans. In a
Portuguese population, HLA-B*58:01 was seen in 63%
(12/19) of allopurinol-induced DReSS/DiHS cases, having
an OR of 85.36 (95% CI 32.52–224.04) when it was com-
pared with a healthy population [38]. A study in Taiwan
with 51 allopurinol-induced severe cutaneous adverse drug
reactions (SCARs) cases, which included 30 DReSS/DiHS
patients, showed that the HLA-B*58:01 allele was found in
all 51 patients, but only in 15% (20/135) of tolerant patients
(OR = 580.3, 95% CI 34.4–9780.9; p = 4.7 × 10−24) [39].
The HLA-B*13:01 allele was associated with dapsone
hypersensitivity in Chinese leprosy patients. It was present
in 86% (65/76) of the patients but in only 14% (148/1034)
of the controls, reporting an 85.5% sensitivity and 85.7%
specificity (OR = 20.53; p = 6.84 × 10−25). This means that
absence of the allele is expected to reduce the risk of the
dapsone hypersensitivity by a factor of 7 (from 1.4% to

Table 2 Human leukocyte antigen association with drug reaction with eosinophilia and systemic symptoms (DReSS)/drug-induced hypersensi-
tivity syndrome (DiHS)
Associated drug HLA allele
Allopurinol B*58:01
Carbamazepine A*31:01
Dapsone B*13:01
Lamotrigine A*24:02
Nevirapine C*04:01
Phenytoin B*51:01
B*15:13
CYP2CP9*3
Modified from Chen et al. [176] and Litt’s Drug Eruption and Reaction Manual [177]
CYP cytochrome P450, HLA human leukocyte antigen
0.2%) [40]. A recent systematic review reported an associa-
tion between HLA-B*13:01 and two Chinese populations
and one Thai population [41]. Another HLA recognized as a
risk factor for drug hypersensitivity is HLA-C*04:01, which
is associated with nevirapine in the Malawian population
[42] (Table 2).
4.2 Immune Response
Drug-specific T  cells play an important role in DReSS/
DiHS, as observed in other severe drug eruptions. Three
different models have been proposed that could explain the
relationship/interaction between a drug or its metabolites
with the immune system: the hapten/pro-hapten model,
pharmacological interaction (p-i) model, and altered peptide
repertoire model [43]. In the first model, antigen (Ag)-pre-
senting cells would present the drug or its metabolites as a
foreign Ag. In the p-i model, it is hypothesized that drugs or
metabolites can bind non-covalently to major histocompat-
ibility complex (MHC) proteins or T cell receptors (TCRs)
in a peptide-independent manner to elicit T cell responses. In
the altered peptide repertoire model, drugs and metabolites
bind directly to the binding groove of MHC proteins, chang-
ing the peptide specificity of MHC binding. These peptides
are then recognized as foreign and evoke T cell responses.
It is important to remember that neither of these proposed
mechanisms is specific for DReSS/DiHS, but rather to all T
cell immune-mediated adverse reactions, such as SJS/TEN,
acute generalized exanthematous pustulosis (AGEP), and
maculopapular eruption.
4.3 Viral Reactivation
As HHV can be detected in the blood of approximately
60–80% of patients with DReSS/DiHS at some timepoint
during the course of the disease, HHV-6 reactivation has
S. A. Martínez-Cabriales et al.
Ethnicity
Han Chinese, Thai, Japanese, Korean, European
Han Chinese, European, Spanish, Northern
European, Japanese, Korean
Han Chinese
Spanish
Malawian
Thai
Malaysian
Han Chinese, Japanese, Malaysian
been included in the diagnostic criteria for DReSS/DiHS
developed by Japanese experts [44–46]. Regardless of
that observation, reactivation of HHV-6 is not essential
for DReSS/DiHS to manifest, but it could be an aggravat-
ing factor in the course of the disease, and it has been pro-
posed as a marker of severity for the disease [47]. In 2007,
Tohyama et al. [47] published a study in which they linked
HHV-6 reactivation in the flaring and severity of DReSS/
DiHS. In 2010, Picard et al. [48] supported the hypoth-
esis that the culprit drugs may cause viral reactivation,
proliferation, and antigenic presentation of herpes viruses
in cells such as B lymphocytes, inducing a multi-organ
immune response in a susceptible individual. It remains to
be resolved why sequential reactivation of herpes viruses
specifically occurs in DReSS/DiHS. One hypothesis is that
the expansion of the regulatory T cells (Tregs) during the
acute stage of DReSS/DiHS might lead to an increased
reactivation of herpes virus [49].
According to Shiohara et  al. [50], HHV-6 DNA is
detected in serum about 3–5 weeks after disease onset,
with subsequent increased titers in the IgG levels. How-
ever, no useful predictive marker of HHV-6 reactivation
has yet been widely accepted [51]. Some of the biomark-
ers that seem to correlate with HHV-6 reactivation are
tumor necrosis factor (TNF)-α, interferon (IFN)-induced
protein 10, C-X-C motif chemokine 10 (CXCL10), thymus
and activation-regulated chemokine and other T helper
(Th) 2-type cytokines/chemokines, plasmacytoid dendritic
cells, and high-mobility group box (HMGB)-1 [51].
Although there is no consensus as to whether the initia-
tion of antiviral medications should be recommend, it is
proposed that HHV-6, HHV-7, cytomegalovirus (CMV),
and Epstein-Barr virus viral antibody titers and viral loads
should be assessed in individuals with DReSS/DiHS at 1-
to 2-week intervals, particularly in severe cases or if the
DReSS: How Far Have We Come?
Table 3 Association of organ injury and culprit drug
Organ Associated drug
Kidneys Allopurinol [55]
Lungs Minocycline [55, 58], abacavir [58]
Heart Minocycline, ampicillin [134],
sulfonamides [140]
patient is not improving rapidly on systemic corticosteroid
monotherapy [52].
4.4 Clinical Features
DReSS/DiHS presents with a combination of fever, diffuse
rash, and signs of organ involvement [44] (Table 3), which
are key to its diagnosis. The disease usually presents itself
within 2 months after the introduction of the culprit drug,
with a range of time between the initiation of the drug and
the onset of DReSS/DiHS of 3 weeks to 3 months [50].
Fever (38–40  °C) is the most common sign (seen in
90–100% of cases), followed by a skin rash (87% of cases)
[53]. The skin rash usually involves more than half of the
body surface area and may even develop into erythroderma.
The cutaneous lesions are frequently of polymorphic pres-
entation, described as maculopapular, urticarial, exfolia-
tive, lichenoid, pustular, bullous, target-like, or eczema-like
lesions [54]. Facial edema has been reported as frequently as
in 76% of cases, which constitutes a warning sign, because
in common cutaneous adverse drug reactions the face is usu-
ally spared [29, 55, 56]. Mucosal involvement, mainly of the
lips and oral cavity, can be present in 56% of cases [29, 57].
Different organs and systems can be affected during
DReSS/DiHS. Hematological abnormalities are usually
observed, eosinophilia being most common (95%), followed
by neutrophilia (78%), monocytosis (69%), and atypical lym-
phocytes (67%); lymphadenopathy has been identified is as
many as 54% of patients [29, 55, 58]. The most commonly
affected organ is the liver (75–94%), followed by the kidneys
(12–40%), lungs (one-third of cases), heart (4–27%), and
neurological system (headaches, seizures, coma, and motor
function impairment) [59, 60].
As reported in the literature, eosinophilia, lymphadenopa-
thy, fever, and liver injury have been significantly associated
with a ‘probable/definitive’ case of DReSS/DiHS according
to the RegiSCAR’s scoring system. The same study revealed
that skin rash and liver damage are the most common clini-
cal features associated with DReSS/DiHS, and eosinophilia
is the third most frequently reported sign in this condition
[46].
Organ involvement, based on a clinical investiga-
tion, including medical imaging, electroencephalogram
(EEG), biopsy, and blood work, is part of the criteria at the
RegiSCAR scoring system [61] (Table 4). Certain drugs
have been related to specific organ damage (Table 3).
Generally, atypical lymphocytosis, if present, is early and
eosinophilia is late during each reaction. Both can occur
in the same patient. It is also important to mention that
patients with DReSS/DiHS will often present with subse-
quent flare-ups after the initial episode, and, therefore, with a
prolonged course that can last up to 1 year [62]. Picard et al.
[63] reported a series of 60 patients with DReSS/DiHS, 15
of whom (25%) presented at least one relapse, characterized
by cutaneous lesions. These flare-ups have been associated
with the viral reactivation of HHV-6 [47]. Nevertheless, a
more pronounced lymphocytosis, presence of mononucleo-
sis, and more severe hepatic cytolysis have been suggested
to be a more important viral-dependent reaction in prolonged
DReSS/DiHS [62].
5 Differential Diagnosis
One of the most difficult differential diagnoses is SJS/
TEN, which is a SCAR and clinically manifests with fever,
a skin eruption, and systemic symptoms. In SJS/TEN, the
onset of symptoms tends to appear between 3 and 21 days
after the patient has started the drug, which is a shorter
period of time after the medication was initiated than in
DReSS/DiHS. However, there is not a substantial differ-
ence in this period of time, making it hard to differenti-
ate DReSS/DiHS from SJS/TEN [64]. Fortunately, there
are distinguishing features that allow this differentiation.
For instance, SJS/TEN is characterized by the presence of
detachable skin while DReSS/DiHS presents as a morbil-
liform or maculopapular rash instead. DReSS/DiHS may
have some blisters as a consequence of the pressure of the
surrounding edema. In contrast to SJS/TEN, DReSS/DiHS
histopathology does not show the epidermal necrosis com-
monly seen in SJS/TEN. In addition, the presence of eosin-
ophilia and atypical lymphocytosis will support a DReSS/
DiHS diagnosis instead of SJS/TEN. Also, the multiple
organ involvement behaves differently between them. For
instance, hepatitis and tubule interstitial nephritis are seen
in DReSS/DiHS, while liver and kidney injury manifests
as increased liver enzymes and prerenal azotemia in SJS/
TEN. An overlap of DReSS/DiHS and SJS/TEN should
be diagnosed when a case fulfills the criteria for a definite
or probable diagnosis of the two SCARs, according to the
scoring systems. In 2012 a retrospective study reported
a 2.1% prevalence of true overlap syndromes from 145
confirmed SCAR cases. They found just three overlap-
ping SCARs, in which DReSS/DiHS was the common
denominator; one case was a DReSS/DiHS/AGEP overlap
and two cases were DReSS/DiHS and SJS/TEN overlaps
[65]. Furthermore, some authors suggest retaining the
 S. A. Martínez-Cabriales et al.

Table 4 Diagnostic validation score system of potential cases of drug reaction with eosinophilia and systemic symptoms (DReSS)/drug-induced
hypersensitivity syndrome (DiHS) by Kardaun et al. [61]
RegiSCAR criteria Scorea

1. Fever ≥ 38.5 °C No = – 1; yes = 0

2. Enlarged lymph nodes ≥ 2 different anatomic locations No/unknown = 0; yes = 1
3. Eosinophilia
 Eosinophils (absolute count) No = 0; eosinophils 0.7–1.49 × 109/L = 1; eosino-
phils ≥ 1.5 × 109/L = 2
 Eosinophils, if leukocytes < 4 × 109/L No = 0; eosinophils 10–19.9% = 1; eosinophils ≥ 20% = 2
4. Atypical lymphocytes No = 0; yes = 1
5. Skin involvement
 Body surface area > 50% No = 0; yes = 1
 Skin rash suggesting DReSS No = –1; unknown = 0; yes = 1
 Biopsy suggesting DReSS No = –1; yes = 0
6. Organ involvementb
 Liverc, kidneyd, lung, muscle/hearte, pancreasf, and other organ(s) No = 0; 1 organ = 1; ≥ 2 organs = 2
7. Resolution ≥ 15 days No = –1; yes = 0
8. Evaluation other potential causes:
 ANA None positive and ≥ 3 negative = 1
 Blood culture
 Serology for HAV/HBV/HCV/ Chlamydia/Mycoplasma pneumoniae
 Other serology/PCR

ANA antinuclear antibody, CPK creatine phosphokinase, CPK-MM creatine phosphokinase indicative for skeletal muscle, CPK-MB indicative for
heart muscle, GFR glomerular filtration rate, HAV hepatitis A virus, HBV hepatitis B virus, HCV hepatitis C virus, PCR polymerase chain reac-
tion, RegiSCAR European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples, UNL upper normal
limit
Potential cases of DReSS/DiHS: hospitalized patients with a reaction suspected to be drug related, with ≥ 3 of the following features: (1) acute
skin rash; (2) fever > 38  °C; (3) enlarged lymph nodes in at least 2 different body sites; (3) involvement of at least 1 internal organ; and (4)
blood count abnormalities (lymphocytes above or below the laboratory limits, eosinophils above the laboratory limits [in percentage or absolute
count], platelets below the laboratory limits) [61]
a
Minimal score − 4, maximal score 9. Final score < 2 = no case; 2–3 = possible case; 4–5 = probable case; > 5 = definite case
b
Organ involvement if
c
liver enzymes elevated > 2 × UNL on ≥ 2 successive dates;
d
creatinine > 1.5 times usual value on ≥ 2 successive dates and/or proteinuria above 1  g/day, haematuria, decreased creatinine clearance,
decreased GFR;
e
raised serum CPK > 2 × UNL. Raised isoenzymes. Serum troponin T > 0.01 µg/L;
f
amylase and/or lipase ≥ 2 × UNL

SJS/TEN diagnosis instead of DReSS/DiHS, especially if
patients presents with fever, rash, and severe internal organ
involvement; this not only takes into account that SJS/TEN
has a poorer prognosis with a high mortality rate but also
considers that the most important factor for mortality in
DReSS/DiHS is the development of TEN [66].
The two major fundamental differences between DReSS/
DiHS and AGEP are the morphology of the skin lesions
and the period of latency between the drug exposure and
appearance of symptoms [46]. In contrast to DReSS/DiHS,
AGEP presents with an abrupt onset of fever along with the
appearance of multiple tiny sterile pustules disseminated all
over the skin surface that appear within the first 3 days of
drug exposure. If a delayed drug reaction fulfils criteria for
both AGEP and DReSS/DiHS, we agree with other authors
regarding describing it as DReSS/DiHS with AGEP features
or a DReSS/DiHS/AGEP overlap [67].
Mycosis fungoides and Sézary syndrome present with
multiple scaly erythematous patches/plaques or general-
ized erythroderma, respectively. Hepatosplenomegaly,
lymphadenopathies, and B cell symptoms may be present.
Sézary syndrome is characterized by neoplastic T cells in
the skin and peripheral blood (at least 1000 cells/µL) and/
or increased CD4 + lymphocytes with a CD4/CD8 ratio ≥ 10
in the peripheral blood, and a clonal TCR rearrangement in
the blood identified by polymerase chain reaction (PCR) or
Southern blot analysis are present [68]. These skin disorders
may have additional cutaneous manifestations such as pal-
moplantar hyperkeratosis, infiltrated plaques, and exophytic
tumors.
DReSS: How Far Have We Come?
Another differential diagnosis is hypereosinophilic
syndrome, which manifests with marked eosinophilia
(≥ 1500 cells/µL) and eosinophil-mediated multiple-organ
damage, without the context of a drug exposure. The skin
involvement may be seen as urticaria, eczema, or erythro-
derma [69].
Adult-onset Still disease (AOSD) is a multisystem inflam-
matory condition of unknown etiology [70]. It manifests
clinically with spiking fevers, transient maculopapular rash,
lymphadenopathy, hepatosplenomegaly, polyarthralgia,
and sore throat. In complicated cases, patients may develop
pericarditis, hemophagocytic syndrome, and/or chronic
arthropathy [71]. Laboratory tests show an increase in ferri-
tin, erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP), and leukocytosis with a predominance of neutrophils
[72]. Multiple diagnostic or classification criteria have been
proposed, the Yamaguchi criteria being the most widely
accepted; however, AOSD is a diagnosis of exclusion [73].
6 Diagnosis
DReSS/DiHS is a diagnosis sui generis; however, misdi-
agnosis is common. In 1996, Bocquet et al. [17] proposed
a diagnostic criteria comprising just three features: skin
eruption; eosinophilia ≥ 1.5 × 109/μL; and internal organ
involvement signified by transaminase elevation ≥ 2 times
normal, lymphadenopathy > 2 cm in diameter, or nephritis,
interstitial pneumonia, or carditis [17].
In 2006, a Japanese group proposed a diagnostic score
that included the presence of HHV-6 reactivation as a crite-
rion [45, 50]. They found that HHV-6 IgG titers and DNA
usually are detected 2–3 weeks after onset of the rash. They
suggested that HHV-6 reactivation might be a cause of
hypersensitivity syndrome. The association between HHV-6
reactivation and DReSS/DiHS has been described by several
authors since 1997 [19–21]. Tohyama et al. reported two
DReSS/DiHS cases where HHV-6 antibodies were detected
more than 2 weeks after the onset of the disease and while
the patients were in the hospital. They also reported the pres-
ence of DNA on the skin biopsy in one patient [20].
In 2007, the RegiSCAR group developed a scoring sys-
tem for DReSS/DiHS diagnosis after a multinational study
in Austria, France, Germany, Israel, Italy, and the Nether-
lands (Table 3). In this study, DReSS/DiHS was diagnosed
if the patient was hospitalized because of a suspected drug-
related reaction, and at least three of the additional following
criteria were met: acute skin rash, fever, lymphadenopathy
of at least two sites, an involvement of at least one inter-
nal organ, lymphocytosis or lymphocytopenia, peripheral
eosinophilia, and thrombocytopenia. Based on this scoring
system, patients were classified into definite, probable, pos-
sible, or no diagnosis of DReSS/DiHS [61].
In summary, the few differences between the Japanese
validation criteria and the RegiSCAR criteria for DReSS/
DiHS are skin eruption developing after 3 weeks of exposure
to a limited number of drugs and HHV-6 reactivation as
diagnostic criteria in the Japanese criteria; and skin biopsy,
resolution after at least or following 15 days, other organ
involvement besides the liver, and evaluation of other poten-
tial causes as the RegiSCAR criteria.
6.1 Causality Assessment
Proper identification of the culprit drug is of utmost impor-
tance not only to know to avoid them to prevent new epi-
sodes of DReSS/DiHS, but also correct identification of the
causal medication helps identify drugs not related to these
severe drug reactions and encourages the patient to continue
them.
Throughout the years, multiple methods for assessing
causality, including expert judgment or global introspec-
tion, operational algorithms, and probabilistic approaches,
have been designed [74]. In 1976, the Karch-Lasagna algo-
rithm was proposed as an assessment tool to pursue system-
atic evaluation of an adverse drug reaction [75]. In 1980,
Naranjo and colleagues [76] designed a method for assess-
ing the probability of adverse drug reactions with a scored
questionnaire of ten parameters, in which each question has
three answer options: ‘Yes’, ‘No’, or ‘Do not know’ [76].
The results are categorized depending on the total score as
follows: definite if ≥ 9; probable if 5–8; possible if 1–4; and
doubtful if ≤ 0. This scale was consensually validated by
three experts, six raters, and by a good correlation found
with another algorithm [77]. In 1982, Jones [78] described
an algorithm for adverse events validated by the FDA, which
is based on the assessment of four parameters: the temporal
relationship within the drug and the adverse event, dechal-
lenge, challenge, and evaluation of a confounding disease.
The Bayesian Adverse Reactions Diagnostic Instrument
(BARDI), which assesses several serious adverse events,
including hypersensitivity skin reactions, has been used con-
sistently [79–82]. BARDI includes epidemiologic and clini-
cal data and gives a probability result between 0 (unlikely)
and 1 (certainty) [83, 84]. Currently, with computational
techniques, the Bayesian network is a tool that allows cau-
sality assessment to be carried out in a pharmacovigilance
center [82].
Unfortunately, there is not a specific algorithm of cau-
sality of DReSS/DiHS as there is for SJS/TEN [85]. Inter-
estingly, the ALDEN (algorithm of drug causality for epi-
dermal necrolysis) algorithm takes the elimination half-life
value of the drugs into consideration to avoid the incorrect
impression that symptoms may not be secondary to a drug
reaction if the drug has been withdrawn from the patient’s
medication regimen before the onset of the symptoms. For

instance, it is important to be aware that patients on allopuri-
nol can develop symptoms 2 weeks after the drug is stopped
because allopurinol and/or its metabolites are slowly cleared,
especially if the patient has renal insufficiency. In addition,
a systematic review of allopurinol-induced DReSS/DiHS
reported long periods of time between the clinical manifesta-
tions and the starting of the allopurinol, with 90% (489/538)
of the cases within 8.6 weeks (60 days) [86]. Another study
reported a latency time of 25.7  weeks (or 180  days) in
allopurinol-induced DReSS/DiHS [87].
A study by Shear [88], which had an objective of organ-
izing our initial thoughts on the topic, reported a stepwise
approach to a suspected adverse reaction. In addition,
Kardaun et al. [29] recommend a series of steps to exclud-
ing unlikely drugs: (a) drugs taken for more than 3 months;
b) drugs stopped more than 2 weeks before the index day;
and (c) drugs just initiated less than 3 days before the prob-
able index day [29]. Afterward, an expert panel classified the
suspected remaining drugs as ‘very probable,’ ‘probable,’
‘possible,’ and ‘undetermined’ according to the likelihood
reported in the literature.
6.2 Patch Testing
Patch testing (PT) is a safe in vivo test used to identify the
causative drug of a hypersensitivity syndrome [89]. This
method consists of applying the drug, previously diluted in a
media (petrolatum sp., water, or ethanol), on the skin, along
with the media alone used as a control [90]. It is recom-
mended the commercialized form of the drug be tested, as
well as the pure active substance. Several guidelines for PT
relating to drug reactions recommend testing the commer-
cialized drug diluted at 30% and the pure substance at 10%,
both in petrolatum sp. and water [91, 92]. The European
Society of Contact Dermatitis (ESCD) recommends using
the powder from intravenous preparations or capsules from
the drugs used by the patients to prepare the in-house PT
material into an active principle in a final 10% (wt/wt) dilu-
tion [93]. On the other hand, as other authors have reported
drug reaction symptoms occurring after PT to aciclovir, car-
bamazepine, or pseudoephedrine, they recommend starting
the first dilution of the drug at 0.1% and, if negative, increas-
ing it up to 10% [94–96].
PT should be performed on the sites that were previously
affected. Several reported cases showed negative results
from PT when they were applied on the back, but positive
results in the same patients when the tests were performed
on the most highly affected cutaneous sites [91, 97, 98].
According to the International Contact Dermatitis Research
Group (ICDRG), a test looking for a local reaction should
be read at 48 and 96 h and, if negative, on day 7 [93, 99,
100]. PT should be performed during the 6 months follow-
ing DReSS/DiHS and 1 month after any immunosuppressive
S. A. Martínez-Cabriales et al.
treatment [91, 101]. Unfortunately, there is not enough evi-
dence regarding the influence of immunosuppressive drugs
on the outcome of the PT [102]. A randomized double-blind
study found that 20 mg/day of oral prednisone suppressed
PT reactivity in patients hypersensitive to nickel [103]. A
prospective study reported positive PT reactions in patients
on azathioprine, cyclosporine, mycophenolate mofetil, meth-
otrexate, infliximab, adalimumab, etanercept, and tacroli-
mus [102]. The ESCD guidelines recommend being aware
of false-negative reactivity in patients on immunosuppres-
sive therapy and to postpone PT if possible [93]. Because
of the lack of a well-standardized PT method, the sensitivity
and specificity are yet unknown. One study reported that the
positive predictive values were higher than the negative pre-
dictive values, and that they were high as 80–90% for certain
drugs such as carbamazepine, but only around 10–20% for
other medications such as phenobarbital. These differences
were attributed to technical and toxicokinetic characteristics
of the drugs [90, 104]. Two other studies reported positive
rates of PT of 64% (46/72) and 32.1% (18/56) using the
same method described by the ESCD guidelines [105, 106].
In both studies, the lack of positive results to allopurinol
causing false-negative results was noticed. Barbaud et al.
[105] also reported negative PT results to salazopyrin in five
patients. Interestingly, in this study there was a patient who
had a positive PT to carbamazepine and cloxacillin 11 years
after his first PT, and multiple drug reactivity to different
classes of drugs was reported in 18% (13/72) of DReSS/
DiHS [105].
6.3 Confirmation of Causality
The lymphocyte transformation test (LTT) and the meas-
urement of drug-specific IFN-γ-releasing cells by enzyme-
linked immunospot (ELISpot) assay are experimental meth-
ods that help to identify the culprit drug. These methods
require specific expertise and are not part of the diagnostic
routine. In an international consensus of in vitro methods
for the diagnosis of drug hypersensitivity reactions by the
European Network on Drug Allergy (ENDA) and European
Academy of Allergy and Clinical Immunology (EAACI), a
grade C recommendation was given to each of these methods
[107].
6.4 Lymphocyte Transformation Test
The LTT is an in vitro standard laboratory method that helps
to identify the culprit drug in drug-induced hypersensitivity
reactions. This test measures the T cell proliferation, specifi-
cally the H-thymidine, in response to a drug after incuba-
tion [108]. The advantage of the LTT over PT is that can
detect drug reactions caused not only by a delayed hyper-
sensitivity but also by other immunopathologic mechanisms;
DReSS: How Far Have We Come?
however, the combination of both tests is best to determine
the causative drug. The appropriate time to perform the LTT
is 4–8 weeks after remission in order to elude high prolif-
eration of spontaneous cells [109]. There have been cases
that obtained positive results even 10 years later; however,
it is also known that some cases will lose reactivity within
4 years. Because its sensitivity is in the range of 60–73%,
a negative result cannot rule out a drug hypersensitivity
syndrome [108, 110, 111]. On the other hand, this test has
specificity rates of at least 85% [108, 111].
6.4.1 Drug-Specific Interferon-γ-Releasing Cells by ELISpot
Assay
In a study by Takahashi et al. [49] an expansion of functional
Tregs was found in the acute stage of DReSS/DiHS [49].
In their investigation, they reported an increase in IFN-γ
and TNF-α in peripheral blood mononuclear cells (PBMCs)
when stimulated with relevant drug Ag in vitro. They then
analyzed the effect of depletion of Tregs on cytokine pro-
duction by drug Ag-specific effector cells. In this scenario,
a dramatic increase in IFN-γ and TNF-α was documented
under basal or Ag-stimulated conditions, but only during the
acute stage. This demonstrated the importance of Tregs in
cytokine production.
The IFN-γ ELISpot assay is an in vitro technique that
measures the IFN-γ released by cells in DiHS. In this
method, PBMCs from the patient are cultured in the pres-
ence of the suspected drug, causing previously sensitized
lymphocytes to proliferate and release IFN-γ, which will be
detected by the ELISpot assay [112]. This method has been
proposed for used in the acute phase of the hypersensitiv-
ity when is urgent to determine the culprit drug [113]. One
study showed a significant correlation between this method
and LTT (r = 0.65, p < 0.01) [114]. Another study reported
a significant correlation between these two methods in
patients with a history of β-lactam-induced maculopapular
rash [115]. Klaewsongkram et al. [116] reported that this
method was immunogen specific for allopurinol in allopu-
rinol-induced SCAR patients and showed a sensitivity and
specificity of 79% and 95%, respectively [116].
6.5 Histopathology
DReSS/DiHS histopathology is variable [117–120]. It is
described as spongiotic dermatitis and as an exanthematous
drug reaction that commonly has eosinophils and apoptotic
keratinocytes [118, 121, 122]. The histologic features seen at
the epidermis are orthokeratosis, parakeratosis, acanthosis,
spongiosis, and lymphocyte exocytosis. Subcorneal pustules
have also been described [120] and vacuolization of the basal
layer involving the adnexae is commonly seen. At the der-
mis, band-like and/or perivascular inflammatory infiltrates
of lymphocytes CD8 + , cytotoxic granzyme B + lympho-
cytes, Forkhead box P3 + (FOXP3+) Tregs, plasma cells,
eosinophils, and neutrophils are usually present. Eosinophils
are not expected to be present in all cases, even in patients
who have peripheral eosinophilia. Atypical lymphocytes
with hyperchromatic nuclei have been described in different
series [123]; however, a genetic clonal mutation has not been
found [120]. Other common histologic findings are dermal
edema, dilated blood vessels, and extravasated erythrocytes.
Vasculitis is not a feature; however, nuclear debris has been
observed in some biopsies [120].
A study reported that the presence of several inflamma-
tory patterns in a single biopsy is a clue pointing towards
DReSS/DiHS [120], the most common being the association
of the eczematous and interface patterns (20%), followed by
the association of interface dermatitis and erythema multi-
forme-like dermatitis (14%), and, finally, the least common
was the combination of interface dermatitis, eczematous
dermatitis, and AGEP-like histopathology [120]. Another
histologic pattern recently described by Chiou et al. [119]
is the pseudolymphoma pattern, which consists of large
lymphoid cells with hyperchromatic nuclei in the epider-
mis, upper dermis, and around superficial dermal vessels.
Clinic pathological correlation has been reported between
the epidermal necrosis and liver damage as well as renal
disease [120, 124].
7 Management
Initial management of DReSS/DiHS requires a withdrawal
of the culprit drug, replacement of intravenous fluids, cor-
rection of acid–base and electrolyte disturbances, a hyper-
caloric diet, and a multidisciplinary evaluation. Additional
management includes preventing and/or treating any bacte-
rial superinfection and providing adequate skin care.
Corticosteroids remain the mainstay treatment for this
condition. Several reported case series and cases have docu-
mented their efficacy; however, no clinical trials have sup-
ported either corticosteroids or other therapies in DReSS/
DiHS (Table 5). A study suggested that topical corticoster-
oids alone may be considered for the management of milder
forms of DReSS/DiHS based on fewer relapses and fewer
in hospital days in these patients in comparison to those on
systemic corticosteroids; however, a death was seen in this
group [125]. Uhara et al. [126] reported a case series of ten
DReSS/DiHS patients treated without systemic corticoster-
oids who experienced full recovery after 7–37 days without
systemic complications. Three received topical corticoster-
oids along with hydration, and the rest received only hydra-
tion. Two more patients were included in the study, but one
dose of 40 mg of dexamethasone and prednisolone treatment
for rheumatoid arthritis was given to these patients [126].
Table 5 Original articles with drug reaction with eosinophilia and systemic symptoms (DReSS)/drug-induced hypersensitivity syndrome (DiHS) treated by systemic corticosteroids
Author (study location, year)
Chiou et al. (Taiwan, 2008) [119]
Mansur et al. (Turkey, 2008) [178]
Eshki et al. (France, 2009) [127]
Ben m’rad et al. (France, 2009) [70]
Chen et al. (Taiwan, 2010) [28]
Um et al. (Korea, 2010) [171]
Ang et al. (Singapore, 2010) [179]
Wongkitisophon et al. (Thailand, 2012) [174] 27 (M: 14; F: 13)
Sultan et al. (India, 2014) [180]
Funck-Brentano et al. (France, 2015) [125]
Avancini et al. (Brazil, 2015) [181]
Pts Treatments
30 (M: 15; F: 15) SS (IV hydrocortisone initially and changed to oral
prednisone): 22 (76%) pts
Oral antihistamines and supportive therapy: 7 (24%)
pts
TS: 30 pts
31 (M: 15; F: 16) SS (methylprednisolone 32–80 mg/day): 27 pts
TS + antihistamines: 3 pts
15 (M: 5; F: 10) SS: 10 (67%) pts
IVIG in addition to corticosteroid therapy: 3 (20%)
pts
Liver transplant: 1 (6.7%) pt
24 (M: 12; F: 12) SS: 11 pts (Prednisone 0.3–1 mg/kg/day tapered over
4–12 months)
60 (M: 26; F: 34) SS (IV methylprednisone 40–120 mg/day or oral
prednisolone 30–60 mg/day): 45 pts (75%)
IVIG: 2 pts in addition to corticosteroids (1 recovered
and 1 died)
Antibiotics: 6 pts
Supportive care + antihistamines: 10 pts
38 (M: 18; F: 20) SS: 16 pts (42.1%)
TS + antihistamines: 22 (57.9%) pts with complete
recovery
27 (M: 12; F: 15) SS (IV or oral): 25 (92.6%) pts of whom 17 had oral
prednisone 0.5 mg/kg/day and 2 pts at 1 mg/kg/day;
4 had IV hydrocortisone, 1 IV methylprednisolone,
and 1 was on prednisolone 5 mg/day
TS: 2 pts
SS (IV dexamethasone 15–20 mg/day or oral predni-
solone 0.5–0.7 mg/kg/day): 23 (85.2%) pts
Supportive therapy: 4 pts (corticosteroids were
avoided due to HIV infection)
17 (M: 8; F: 9) SS: 17 pts (dexamethasone IV equivalent to pred-
nisolone 1–1.5 mg/kg/day until the rash and fever
disappeared, then oral prednisolone)
38 (M: 19; F: 19) SS: 13 pts (methylprednisolone: 10; oral prednisone:
3)
TS: 25 (66%) pts
27 (M: 17; F: 10) SS: oral prednisone 1 mg/kg/day in all pts; 3 pts
required dose to be increased to 1.5 mg/kg/day and
1 was switched to IV methylprednisolone)
Mortality (%) Cause of death
10 Supportive therapy: 1 died from staphylococcal
pneumonia with septic shock; 1 died from upper
gastrointestinal tract bleeding
SS: 1 died due to an acute renal failure secondary to
rhabdomyolysis
3 6 (19.4%) pts developed a blister dermatitis: 3 SJS and
3 TEN
1 TEN pt died of sepsis
20 SS: 1 died from myocarditis, hepatitis, and pneumonitis
SS + IVIG: 1 died from multi-organ failure; 1 died due
to hemophagocytosis, rhabdomyolysis, encephalitis,
infection, and pancytopenia
0
10 SS: 1 died due to multi-organ failure, 1 due to cardio-
genic shock, and 1 due to shock with negative blood
cultures
SS + antibiotics: 1 died due to septic shock
SS + IVIG + antibiotics: septic shock
Antibiotics alone: 1 died from septic shock
2.6 SS: 1 died from an opportunistic infection + liver fail-
ure; 1 pt had liver damage but was lost to follow-up
Complete recovery was noted in 36 pts (94.8%)
0
3.7 1 pt died from multi-organ failure and sepsisa
5.9 1 died from hepatic failure
2.63 TS: 1 died due to hypovolemic shock a few weeks after
he was discharged
4 1 died from hepatic failure
S. A. Martínez-Cabriales et al.
Table 5 (continued)
Author (study location, year) Pts Treatments Mortality (%) Cause of death

Min et al. 11 (M: 8; F: 3) SS: 7 pts (IV) and 1 (oral) 18 IV corticosteroid: 1 pt died due to a subdural hem-
(Korea, 2015) [182] TS: 6 pts (5 cases in combination with an SS) orrhage hemodialysis due to azotemia, 1 pt died
Antihistamines: 9 pts (all of them along with an SS) because of pneumonia
Hepatotonics: 3 pts
Wu et al. (China, 2017) [163] 52 (M: 34; F: 18) SS: 20 (38%) pts 6 3 died (SS + IVIG: 2 pts) of multi-organ failure and
SS + IVIG: 32 (62%) pts sepsis
DReSS: How Far Have We Come?

Lee et al. (Korea, 2017) [183]
Matta et al. (Mexico, 2017) [184]
Ichai et al. (France, 2017) [185]
25 (M: 11; F: 14) SS (IV or oral): 13 (52%) pts
SS + IVIG: 2 pts
TS + antihistamines: 12 (48%) pts
11 (M: 4; F: 7) SS: 8 pts (oral prednisone 0.5–1 mg/kg)
Antihistamines: 1 pt
Not specified for the other 2 pts
16 (M: 5; F: 11) NAC: all pts. Loading dose: 50 mg/kg in 1 h then
50 mg/kg in 4 h, then 100 mg/kg/day
SS: 9 pts (2 received oral prednisolone 1 mg/kg/
day and 7 received 500 mg × 3 days), of whom 5
improved and 4 worsened
Liver transplant: 5 pts
12 3 pts died:
IV SS: 1 died due to renal failure
TS + antihistamines: 1 had pneumonia with septic
shock; 1 died because of septic shock
9 SS: 1 died due to sepsis secondary to pneumonia
25 SS: 5 pts improved. The other 4 pts either died or had
liver transplant
1 died from multi-organ failurea; 1 died on the waiting
list for a liver transplanta
After liver transplant: 1 died due to a systemic fungal
infection + hepatic failure + multiple organ failure; 1
died due to chronic rejection

F female, IV intravenous, IVIG intravenous immunoglobulin, M male, NAC N-acetylcysteine, pt(s) patient(s), SJS Stevens-Johnson syndrome, SS systemic corticosteroids, TEN toxic epidermal
necrolysis, TS topical corticosteroids
a
The treatment on which the death of the pt occurred was not specified in the article

In cases with severe organ involvement, systemic cor-
ticosteroid therapy could achieve clinically and laboratory
improvement within a few days; however, in some cases
corticosteroid therapy is not effective or even allows the
disease to flare when the dose is tapered [127]. The recom-
mended dose is 1 mg/kg/day gradually tapered over at least
3 months [128, 129]. The duration of the therapy depends
on the clinical evolution of the patient as well as laboratory
test results. Although it is not needed for most cases, a slow
taper over 3–12 months to avoid flares may be necessary for
some severe clinical presentations [70].
The French Society of Dermatology proposed the follow-
ing treatment algorithm:
(a) In the absence of severity signs, the patient can be man-
aged symptomatically with topical corticosteroid emol-
lients and H1 antihistamines.
(b) In the presence of signs of severity (transaminases
levels > 5 times normal; pneumonia, heart and/or
kidney involvement; and hemophagocytosis), treat-
ment includes systemic corticosteroids equivalent to
1 mg/kg/day of prednisone with a multidisciplinary
approach.
(c) In a life-threatening context such as hemophagocytosis
with bone marrow failure, encephalitis, severe hepati-
tis, renal failure, and respiratory failure, systemic cor-
ticosteroids are recommended with intravenous immu-
noglobulin (IVIG) at a dose of 2 g/kg over 5 days. IVIG
should not be administered in the absence of corticos-
teroids.
(d) In those cases with the presence of severity signs and
confirmation of a major viral reactivation (HHV-6),
systemic corticosteroids plus antiviral medications
(e.g., ganciclovir) with or without IVIG is recom-
mended [128].
Methylprednisolone 30 mg/kg intravenously for 3 days
could be administered as an alternative option to oral cor-
ticosteroids. One case series reported a short recovery of
7–8 days after the use of one pulse of methylprednisolone in
pediatric patients [130]. A pilot study of ten DReSS/DiHS
syndromes treated with pulsed intravenous methylpredni-
solone 500 mg daily for three consecutive days followed by
a 30-day tapering course of oral prednisone starting with
30 mg and tapering 10 mg every tenth day reported a rapid
response to methylprednisolone with a good clinical out-
come but one death after failure of a liver transplant and two
short-term complications: corticosteroid-induced psychosis
on day 31 of corticosteroids and type 1 diabetes mellitus on
day 25 of treatment. The other seven patients did not showed
sequelae during the period of observation of 1–4 years [131].
Considering the use of systemic corticosteroids could pro-
mote viral reactivation (viral reactivation was significantly
S. A. Martínez-Cabriales et al.
higher after treatment with systemic corticosteroids than
after topical treatment [p = 0.06]; increased viral loads of
HHV-6 and CMV have been reported during corticosteroid
treatment [132]), which might be associated with long-last-
ing and relapsing corticosteroid-dependent DReSS/DiHS,
the French Society of Dermatology proposed valganciclovir
use in combination with systemic corticosteroids for those
patients with the presence of severity signs and confirmed
major viral reactivation of HHV-6 [128]. It may be helpful
in minimizing complications related to HHV-6 reactiva-
tion. Asano et al. [133] reported one patient who worsened
on corticosteroids and IVIG and died due to hemorrhagic
shock caused by gastrointestinal bleeding associated with
CMV enterocolitis 34 days after intravenous ganciclovir
200 mg/day was added. In another case where the patient
had received IVIG as a single treatment because of their
medical history of hepatitis C virus infection, the patient
showed improvement in cutaneous ulcers and gastrointes-
tinal bleeding 2 weeks after starting ganciclovir 200 mg/
day [133].
Unfortunately, there is little evidence regarding alter-
native treatments for DReSS/DiHS. Case series and case
reports have reported cyclosporine, IVIG, mycophenolate
mofetil, cyclophosphamide, and rituximab as beneficial
therapeutic options [134]. A case series of two patients
reported a rapid and successful response to short courses
of 3–7 days of cyclosporine (3 days of 5 mg/kg/day and
7 days of 200 mg/day) as a first-line therapy [135]. Other
authors have reported the use of cyclosporine in unrespon-
sive cases to long courses of oral corticosteroids. One sub-
ject with phenytoin DReSS/DiHS was treated with systemic
corticosteroids over 9 months and ultimately responded after
6 months of cyclosporine 4 mg/kg/day [136]. A patient with
DReSS/DiHS due to vancomycin who had not improved
on 2 weeks of corticosteroids achieved improvement after
5 days of cyclosporine 100 mg twice daily [137]. A compli-
cated recurrent DReSS/DiHS with eosinophilic polymyositis
requiring mechanical ventilatory support previously treated
with oral corticosteroids finally responded after combination
therapy of intravenous cyclosporine 100 mg/day, methyl-
prednisolone 60 mg/day, and three IVIG cycles of 1 g/kg/day
for 2 days [138]. Lastly, the patient received an additional
IVIG infusion and was prescribed azathioprine with medium
doses of prednisone, which continued for almost a year until
all laboratory tests were normalized.
On the other hand, fatal outcomes have been reported with
cyclosporine. A case of sulfasalazine-induced DReSS/DiHS
with recalcitrant rash was reported that failed to respond to
systemic corticosteroids and cyclosporine and then devel-
oped into eosinophilic myocarditis, resulting in the death
of the patient 6 weeks after starting the culprit drug [139].
A similar case was reported in a trimethoprim–sulfameth-
oxazole-associated DReSS/DiHS that deteriorated into an
DReSS: How Far Have We Come?
eosinophilic myocarditis, causing the death of the patient
even after combination therapy with IVIG, cyclosporine, and
systemic corticosteroids [134, 140].
IVIG has immunomodulatory and anti-inflammatory
effects. The former therapeutic effect seems to be due to
the presence of antivirus IgG in the IVIG batch, which
could work against herpes virus reactivation, including that
of HHV-6 [141–143]. Several authors support the use of
high doses of IVIG as an adjuvant treatment to corticoster-
oids. The recommended dose for IVIG is 1 g/kg for 2 days
or 2 g/kg over 5 days [128]. A case has been reported of
lamotrigine-induced DReSS/DiHS that had flared twice
when prednisone was tapered down to 10 mg which was
finally successful treated after 4 months of IVIG (0.5 g/kg/
day for 2 days) as an adjuvant therapy [144]. Three cases
have reported a successful outcome with IVIG as mono-
therapy [143, 145, 146]. However, a prospective study does
not support IVIG as a single treatment. This study included
six patients who received 200 mg/kg/day for five consecutive
days. Only one patient achieved a complete response; the
other patients developed a severe adverse effect to the IVIG.
There were two hemophagocytic syndromes, two cases of
malaise that required stopping the IVIG infusion, and one
pulmonary embolus. In the end, oral corticosteroids were
given to two patients with hemophagocytic syndrome and to
two uncontrolled allopurinol-induced DReSS/DiHS patients
[147]. Thus, IVIG as well as pulsed corticosteroid therapy,
although beneficial in the acute stage of DReSS/DiHS, are
aggressive therapies with a risk of dose-dependent adverse
effects. Also, it is controversial whether giving these thera-
pies increases the frequency of autoimmune sequelae.
Mycophenolate mofetil 500 mg twice daily was effec-
tively used as a corticosteroid-sparing agent in a DReSS/
DiHS in a 14-year-old female [148]. Another case reported
the efficacy of mycophenolate mofetil as an adjuvant ther-
apy to IVIG and systemic corticosteroids in a sulfasalazine-
induced DReSS/DiHS that had failed to respond to 4 months
of corticosteroid monotherapy and developed into eosino-
philic myocarditis. The patient required a left ventricular
assist device for 53 days and received maintenance therapy
with mycophenolate mofetil along with lower doses of pred-
nisone for 1 year [140]. A 4-day course of plasmapheresis
and rituximab demonstrated efficacy in a minocycline-
induced DReSS/DiHS with eosinophilic myocarditis in a
patient who was previously unsuccessfully treated with a
high dose of corticosteroids, mycophenolate, and cyclo-
sporine [149]. For maintenance, the patient was put on a
weekly rituximab infusion over a month and continued on
prednisone 15 mg/day and mycophenolate mofetil 1500 mg
twice daily [149].
Cyclophosphamide showed an effective response in an
ibuprofen-related DReSS/DiHS with severe kidney fail-
ure, acute myocarditis, and eye involvement that had been
unsuccessfully treated with 1 month of intravenous and oral
corticosteroids. One pulse of 750 mg/m2 of intravenous
cyclophosphamide was given and 11 days later was switched
to 100 mg/day orally for 6 months, when full recovery was
achieved [150]. In DReSS/DiHS complicated with severe
respiratory distress and myocarditis that required mechani-
cal ventilatory support and cardiovascular reanimation, a
response was seen 12 h after the first of four plasmapheresis
sessions, which were performed every other day along with
systemic corticosteroids [151].
One case has been reported of a beneficial response in the
skin rash and liver involvement of N-acetylcysteine (10 g
intravenously followed by 2.5 g every 6 h for the next 3 days)
as a first-line therapy in a sulfasalazine DReSS/DiHS that
was previously diagnosed as acetaminophen toxicity. When
DReSS/DiHS was diagnosed, prednisone along with valgan-
ciclovir was added for 3 months. The authors suggest that
N-acetylcysteine might work by limiting the drug-derived
reactive metabolites [152]. However, its beneficial effect was
not demonstrated in another sulfasalazine DReSS/DiHS case
[153]. N-acetylcysteine efficacy was also reported in an anti-
convulsant-induced DReSS/DiHS [154], but a case series
reported angioedema as an adverse effect in three patients
2–3 days after intravenous N-acetylcysteine (2 g four times
daily) was administered and when the skin rash associated
with DReSS/DiHS had already been resolved [155].
8 Prognosis
Higher risk of severe organ involvement has been reported
in allopurinol- and minocycline-induced DReSS/DiHS
cases when compared with other drugs [127, 156]. Vis-
ceral involvement comprising multi-organ failure seems
to be unpredictable. HHV-6 reactivation, pancytopenia,
hypereosinophilia > 1500 cells/µL, heart rate > 90 beats/
min, white blood cells > 12,000/mm3, respiratory rate > 20
breaths/min, coagulopathy, gastrointestinal bleeding, and
systemic inflammatory response syndrome are indicators of
poor prognosis [28, 47, 70, 119, 157]. Hepatic dysfunction
appears in 51–87% of cases, and is the most common cause
of death [119, 127, 156, 158]. Heart involvement could
appear even months after DReSS/DiHS and could turn into
a fulminant myocarditis [134, 140].
Infectious diseases including herpes simplex, herpes zos-
ter, CMV, Pneumocystis jirovecii, and cryptococcal pneu-
monia have been reported most commonly within 3 months
after DReSS/DiHS. A study reported two cases of CMV
reactivation thrombotic infarction that occurred within
2 months after DReSS/DiHS [159]. One case was chrono-
logically associated with a large deep venous thrombosis
in the inferior cava vein and bilateral femoral veins [160].
Herpes zoster has been reported to appear between 2 months

and 3 years after the onset of DReSS/DiHS [132, 161]. Kano
et al. [161] reported a herpes zoster prevalence of 11% (3/28)
in a 6-month observation period after DReSS/DiHS, in
which two cases appeared during the tapering of the cor-
ticosteroid dose [161]. Interestingly, a retrospective study
of 34 DReSS/DiHS cases, in which 14 patients received
corticosteroid treatment, reported that most viral infections
(herpes zoster, encephalitis, and CMV) were detected when
the oral corticosteroid dose was decreased to 25–67% of the
initial dose [132]. P. jirovecii pneumonia (2.5 months after)
and cryptococcal pneumonia (2.5 months after) were seen
when the corticosteroid dose was reduced to 50% and 15%
of the initial dose, respectively [132].
Although most patients will achieve complete recov-
ery after withdrawal of the culprit drug, close monitoring
including blood work is required because frequent flar-
ing, late organ involvement, and long-term sequelae may
lead to end-organ failure or autoimmune diseases such as
hyperthyroidism, hypothyroidism, type 1 diabetes, systemic
lupus erythematosus (SLE), autoimmune hemolytic anemia,
and sclerodermoid graft-versus-host disease-like lesions
[119, 132, 144, 162–165]. Autoimmune diseases following
DReSS/DiHS are related to viral infection or reactivation
and dysfunction of Tregs [49, 166, 167].
Chen et  al. [168] reported an incidence of long-term
sequelae of 11.5% (6/52) in DReSS/DiHS, which was
defined as the onset of clearly diagnosed diseases, devel-
opment of end-organ failure after resolution of drug
hypersensitivity, or the onset of disease during the acute
stage that was not resolved after DReSS/DiHS [168]. The
study reported Graves’ disease 36  days and 8.7  months
after DReSS/DiHS in two young patients; alopecia areata
2 years after the DReSS/DiHS; fulminant type 1 diabetes
(FT1DM) 48 days after the DReSS/DiHS; hemolytic ane-
mia 14 days after the DReSS/DiHS in a patient with SLE;
and two patients with underlying hypertension, diabetes,
and chronic renal insufficiency who developed deteriora-
tion of their renal function requiring lifetime hemodialy-
sis 10 days and 2.7 years after DReSS/DiHS [168]. Kano
et al. reported autoimmune thyroid disease as being the
most common sequelae of DReSS/DiHS in 4.8% (7/145) of
cases, followed by FT1DM in 3.45% (5/145) [159]. The time
interval between DReSS/DiHS and thyroid autoimmune dis-
ease—Graves’ disease, Hashimoto thyroiditis, and painless
thyroiditis—is 2 months to 3 years [162, 168]. The FT1DM
appeared within 2 months (mean of 42 days) of onset of
DReSS/DiHS. Other complications were one case each of
vitiligo (4.5 months after), rheumatoid arthritis (10 years
after), lupus erythematosus with severe lupus nephritis
(4 years after DReSS/DiHS in a patient who received IVIG
alone) [165], and thrombotic infarction (2 months after)
[159]. Two patients with underlying renal disease required
lifetime hemodialysis, starting 1 and 5 years after DReSS/
S. A. Martínez-Cabriales et al.
DiHS [159]. Multiple autoimmune sequelae have been seen
in the same patients [169]. Brown et al. [162] reported an
autoimmune thyroiditis, type 1 diabetes, elevated ANA, and
anti-Smith and anti–Sjögren syndrome-A (SS-A/Ro) anti-
body titers after a minocycline-induced DReSS/DiHS [162].
In terms of prognosis, it is unknown whether systemic
corticosteroids improve the survival of DReSS/DiHS
patients. Regarding sequelae, one study documented a dif-
ferent effect of systemic corticosteroids on short-term (less
than 6 months after DReSS/DiHS) and long-term outcomes
of DReSS/DiHS. In the short-term outcome, corticoster-
oids were associated with multiple infections, but in the
long-term outcomes, those patients treated with corticos-
teroids (0.6–1.0 mg/kg daily tapered mostly over 8 weeks)
documented an absence of autoimmune disease, while lupus
erythematosus and autoimmune thyroiditis, along with the
presence of autoantibodies after complete resolution of the
DReSS/DiHS, was seen in those patients who did not receive
corticosteroids [132, 159]. The presence of autoimmune
sequelae might be explained by the decrease in the suppres-
sive function of the Tregs in the resolution phase of DReSS/
DiHS, allowing a higher risk of developing an autoimmune
disease [49].
9 Conclusion
DReSS/DiHS develops in the setting of a complex interac-
tion of genetic, viral, and environmental factors. Although
there are still some questions to be answered regarding
DReSS/DiHS and its physiopathology, the disease is now
well-characterized. The RegiSCAR score allows identifica-
tion of potential cases and classifies them in order to avoid
missing real DReSS/DiHS cases. However, concern has
emerged regarding cases being reported as DReSS/DiHS
without organ involvement because they scored 4 points on
RegiSCAR. For instance, a patient may present with derma-
titis, swollen lymph nodes, and high levels of eosinophilia;
however, these findings can be observed in severe atopic
dermatitis as well. Identifying the disease is imperative to
remove the culprit drug and address potentially fatal com-
plications. Those patients without severe organ involvement
may be treated with topical corticosteroids and supportive
care; however, monitoring of the course of the disease must
be done and if liver, kidney, lung, or other organ injury
develops, systemic corticosteroids should be initiated until
clinical and laboratory normalization, followed by a slow
taper over 3 months. Regarding the benefit of corticoster-
oid treatment in mortality, there is not enough evidence to
allow us to reach specific conclusions, and further studies
are required. However, corticosteroids remain the mainstay
treatment option in severe cases based on the long-term evi-
dence of retrospective studies and case series reported in
DReSS: How Far Have We Come?
the literature. After recovery, the patient should be educated
regarding the culprit drug and there should be long-term
follow-up for identification of possible autoimmune com-
plications. In cases where there is a defined genetic risk,
patients should be tested and encouraged to share that infor-
mation and its relevance with close family members such as
children and siblings.
Lastly, we consider the term DReSS/DiHS to be the most
appropriate acronym to emphasize that the absence of eosin-
ophilia does not exclude its diagnosis. Thus, it is clear that
DReSS/DiHS should be suspected in the appropriate clinical
context, and that a normal eosinophil count does not rule out
DReSS/DiHS.
Compliance with Ethical Standards
Funding No funding was received for the preparation of this review.
Conflict of interest S.A. Martinez-Cabriales, F. Rodriguez-Bolaños,
and N.F. Shear declare that they have no conflicts of interest.
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