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

Vol.:(0123456789)
S. A. Martínez-Cabriales et al.

and phenobarbital. A similar situation occurred with pseu- In comparison with Stevens-Johnson syndrome (SJS)
dolymphoma associated with carbamazepine, Kawasaki-like and toxic epidermal necrolysis (TEN), which have been
disease caused by carbamazepine, and periarteriitis nodosa identified for years in the International Classification of
associated with sulfadiazine [2–10]. Diseases–Clinical Modification (ICD-CM) diagnosis codes,
In 1981, Spielberg et al. [11] reported three cases of DReSS was not identified until the 11th revision of the ICD
“phenytoin hepatitis”. Shear joined this group and recog- in 2018 with the code EH65 [23]. Previously, the code most
nized that each of these patients had a systemic syndrome closely related to the DReSS/DiHS definition was L27; how-
with fever, rash, eosinophilia, liver involvement, and cervi- ever, it was only introduced in October 2015 [24]. This code
cal adenopathy related to phenytoin use [11]. John Stan- included “dermatitis due to chemotherapy, dermatitis due to
ley and Fallon-Pellicci [12] had earlier reported what was drug and/or medicine taken internally, drug rash, eruption
called phenytoin hypersensitivity syndrome. Trying to due to drug, and generalized dermatitis due to drug taken
understand the complex pathogenesis of this idiosyncratic internally” [24].
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 2 Literature Search Methods
drug reaction and that there was a genetic risk. This led to
recognition that more antiepileptic therapies can cause the A review of DReSS/DiHS cases treated with corticoster-
same systemic syndrome and that there was a high risk of oids reported in the literature was carried out by searching
cross-reactivity among the most commonly used antiepilep- PubMed/MEDLINE and EMBASE between January 1990
tic drugs [13]. Furthermore, in 1985, Shear and Spielberg and May 2018. Search terms were “DRESS”, “drug reac-
[14, 15] demonstrated the in vitro production of potentially tion with eosinophilia and systemic symptoms”, “drug rash
toxic metabolites of sulfadiazine, and suggested that these with eosinophilia and systemic symptoms”, “drug hypersen-
could act as haptens, causing a hypersensitivity syndrome. sitivity and eosinophilia”, “drug-induced hypersensitivity
Thus, in 1988, anticonvulsant hypersensitivity syndrome syndrome”, systemic steroid (subheadings: therapeutic use),
was defined for the first time after the study of 53 patients cyclosporine, mycophenolate mofetil, IVIG, cyclophospha-
with clinical hypersensitivity reactions to phenytoin, phe- mide, and rituximab. Publications were limited to the Eng-
nobarbital, and carbamazepine [13]. The authors chose this lish language.
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 3 Epidemiology
fever, skin rash, and internal organ involvement (hepatitis,
nephritis, pneumonitis, pericarditis, and myocarditis), occur- The incidence of DReSS/DiHS has been estimated at 1
ring with a delay of approximately 21 days after the onset of case per 10,000 exposures to selected antiepileptics [25].
the medication [13, 16]. Many reports generally agree that DReSS/DiHS has no age
In 1996, the term “drug rash with eosinophilia and sys- or sex predilection [26], but there have been some reports
temic symptoms (DReSS)” was introduced in France by of certain ethnic groups presenting with a higher incidence
Bocquet et al. [17]. Its use was subsequently internationally [27]. As previously mentioned, DReSS/DiHS can be a life-
accepted, although not everywhere [17]. Shortly after, the threatening condition, with a mortality rate of approximately
authors proposed to substitute reaction instead of rash for the 10% [28]; nevertheless, a 2013 study from the RegiSCAR
‘r’ because “the skin lesions are not a constant feature”, as (European Registry of Severe Cutaneous Adverse Reactions
they explained after the term drug-induced delayed multi- (SCAR) to Drugs and Collection of Biological Samples)
organ hypersensitivity syndrome (DIDMOHS) was proposed study group reported a lower percentage, with two deaths
by Sontheimer and Houpt [18] in 1998. Although this term reported during the acute phase in the 117 patients diag-
was coined in an effort to explicitly point out the delayed nosed with probable or definite DReSS/DiHS [29]. Unfor-
multi-organ involvement, it has rarely been used. At that tunately, even now, many cases are undiagnosed and, there-
time, other investigators noticed the presence of human fore, unregistered, limiting the accuracy of data.
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 4 Pathophysiology
that continue today. In 2006, Japanese investigators used the
term “drug-induced hypersensitivity syndrome” (DiHS), the The physiopathology of DReSS/DiHS is still not completely
diagnostic criteria of which included HHV-6 reactivation understood; nevertheless, thanks to the efforts of multiple
[22]. 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 estimated positive and negative predictive values of 12.7%
to occur in genetically predisposed individuals when they and 98.7%, respectively. In a European study, the presence
are exposed to certain drugs (Table 1). In addition to drug of the HLA-A*31:01 had a sensitivity and specificity of 26%
hypersensitivity, the reactivation of HHVs and subsequent and 96%, respectively. McCormack et al. [32] reported a
antiviral immune responses may also contribute to a higher prevalence of 5% of this allele in Europeans; its presence
severity and a more protracted course of DReSS/DiHS [30]. caused a risk of carbamazepine-induced hypersensitivity
reactions, including DReSS/DiHS, of up to 26%, and its
4.1 Genetic Factors 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
A genetic predisposition for cutaneous drug reactions had patients with DReSS/DiHS were compared with 257 control
been suspected for a long time, but it was in 2002 when the subjects without adverse drug reactions. In Asians, the risk
first clear hypersensitivity reaction associated with specific of developing carbamazepine hypersensitivity was increased
human leukocyte antigen (HLA) subtypes was established nine-fold in those who carried an HLA-A*31:01 [36]. This
[31]. These HLA subtypes have been determined for cer- allele, HLA-A*31:01, appears to be specific for carbamaze-
tain drugs and have been part of the means to prevent drug pine-induced cutaneous adverse drug reactions since it was
reactions in certain populations. HLA-A*31:01 is linked to not relevant for lamotrigine- and phenytoin-induced hyper-
DReSS/DiHS induced by carbamazepine in northern Euro- sensitivity reactions in Europeans [37].
pean, Japanese, southern Chinese, and Korean populations Another drug that has been linked to a specific HLA
[32]. In 2006, Hung et al. [33] published the association is allopurinol, especially to HLA-B*58:01, which is seen
of HLA-A*31:01 in Chinese patients. This allele was seen mostly in Asian populations and some Europeans. In a
in 25.8% (8/31) of those with so-called ‘maculopapular Portuguese population, HLA-B*58:01 was seen in 63%
eruption or exanthem’ (MPE)/hypersensitivity syndrome, (12/19) of allopurinol-induced DReSS/DiHS cases, having
but only in 2.8% (4/144) of the control group (odds ratio an OR of 85.36 (95% CI 32.52–224.04) when it was com-
[OR] = 12.17, 95% confidence interval [CI] 3.6–41.2; pared with a healthy population [38]. A study in Taiwan
p = 0.0021) [33]. In 2011, Kim et al. [34] reported the pres- with 51 allopurinol-induced severe cutaneous adverse drug
ence of the HLA-A*31:01 allele in 58.8% (10/17) of carba- reactions (SCARs) cases, which included 30 DReSS/DiHS
mazepine-induced hypersensitivity cases and in 14% (7/50) patients, showed that the HLA-B*58:01 allele was found in
of the carbamazepine-tolerant controls (OR = 8.8, 95% CI all 51 patients, but only in 15% (20/135) of tolerant patients
2.5–30.7; p = 0.011); this was higher than in the Korean gen- (OR = 580.3, 95% CI 34.4–9780.9; p = 4.7 × 10−24) [39].
eral population (OR = 12.4, 95% CI 4.5–34.1; p = 2.9 × 10−6) The HLA-B*13:01 allele was associated with dapsone
[34]. In the same year, a Japanese study reported the pres- hypersensitivity in Chinese leprosy patients. It was present
ence of HLA-A*31:01 in 60.7% (37/61) of the patients with in 86% (65/76) of the patients but in only 14% (148/1034)
carbamazepine-induced cutaneous adverse drug reactions, of the controls, reporting an 85.5% sensitivity and 85.7%
including DiHS, showing a sensitivity of 60.7% and a spec- specificity (OR = 20.53; p = 6.84 × 10−25). This means that
ificity of 87.1% [35]. They also reported a prevalence of absence of the allele is expected to reduce the risk of the
2.9% of this allele in the Japanese general population, with dapsone hypersensitivity by a factor of 7 (from 1.4% to
S. A. Martínez-Cabriales et al.

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 Ethnicity

Allopurinol B*58:01 Han Chinese, Thai, Japanese, Korean, European


Carbamazepine A*31:01 Han Chinese, European, Spanish, Northern
European, Japanese, Korean
Dapsone B*13:01 Han Chinese
Lamotrigine A*24:02 Spanish
Nevirapine C*04:01 Malawian
Phenytoin B*51:01 Thai
B*15:13 Malaysian
CYP2CP9*3 Han Chinese, Japanese, Malaysian

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- been included in the diagnostic criteria for DReSS/DiHS
tion between HLA-B*13:01 and two Chinese populations developed by Japanese experts [44–46]. Regardless of
and one Thai population [41]. Another HLA recognized as a that observation, reactivation of HHV-6 is not essential
risk factor for drug hypersensitivity is HLA-C*04:01, which for DReSS/DiHS to manifest, but it could be an aggravat-
is associated with nevirapine in the Malawian population ing factor in the course of the disease, and it has been pro-
[42] (Table 2). posed as a marker of severity for the disease [47]. In 2007,
Tohyama et al. [47] published a study in which they linked
4.2 Immune Response HHV-6 reactivation in the flaring and severity of DReSS/
DiHS. In 2010, Picard et al. [48] supported the hypoth-
Drug-specific T  cells play an important role in DReSS/ esis that the culprit drugs may cause viral reactivation,
DiHS, as observed in other severe drug eruptions. Three proliferation, and antigenic presentation of herpes viruses
different models have been proposed that could explain the in cells such as B lymphocytes, inducing a multi-organ
relationship/interaction between a drug or its metabolites immune response in a susceptible individual. It remains to
with the immune system: the hapten/pro-hapten model, be resolved why sequential reactivation of herpes viruses
pharmacological interaction (p-i) model, and altered peptide specifically occurs in DReSS/DiHS. One hypothesis is that
repertoire model [43]. In the first model, antigen (Ag)-pre- the expansion of the regulatory T cells (Tregs) during the
senting cells would present the drug or its metabolites as a acute stage of DReSS/DiHS might lead to an increased
foreign Ag. In the p-i model, it is hypothesized that drugs or reactivation of herpes virus [49].
metabolites can bind non-covalently to major histocompat- According to Shiohara et  al. [50], HHV-6 DNA is
ibility complex (MHC) proteins or T cell receptors (TCRs) detected in serum about 3–5 weeks after disease onset,
in a peptide-independent manner to elicit T cell responses. In with subsequent increased titers in the IgG levels. How-
the altered peptide repertoire model, drugs and metabolites ever, no useful predictive marker of HHV-6 reactivation
bind directly to the binding groove of MHC proteins, chang- has yet been widely accepted [51]. Some of the biomark-
ing the peptide specificity of MHC binding. These peptides ers that seem to correlate with HHV-6 reactivation are
are then recognized as foreign and evoke T cell responses. tumor necrosis factor (TNF)-α, interferon (IFN)-induced
It is important to remember that neither of these proposed protein 10, C-X-C motif chemokine 10 (CXCL10), thymus
mechanisms is specific for DReSS/DiHS, but rather to all T and activation-regulated chemokine and other T helper
cell immune-mediated adverse reactions, such as SJS/TEN, (Th) 2-type cytokines/chemokines, plasmacytoid dendritic
acute generalized exanthematous pustulosis (AGEP), and cells, and high-mobility group box (HMGB)-1 [51].
maculopapular eruption. Although there is no consensus as to whether the initia-
tion of antiviral medications should be recommend, it is
4.3 Viral Reactivation proposed that HHV-6, HHV-7, cytomegalovirus (CMV),
and Epstein-Barr virus viral antibody titers and viral loads
As HHV can be detected in the blood of approximately should be assessed in individuals with DReSS/DiHS at 1-
60–80% of patients with DReSS/DiHS at some timepoint to 2-week intervals, particularly in severe cases or if the
during the course of the disease, HHV-6 reactivation has
DReSS: How Far Have We Come?

Table 3 Association of organ injury and culprit drug RegiSCAR scoring system [61] (Table 4). Certain drugs
have been related to specific organ damage (Table 3).
Organ Associated drug
Generally, atypical lymphocytosis, if present, is early and
Kidneys Allopurinol [55] eosinophilia is late during each reaction. Both can occur
Lungs Minocycline [55, 58], abacavir [58] in the same patient. It is also important to mention that
Heart Minocycline, ampicillin [134], patients with DReSS/DiHS will often present with subse-
sulfonamides [140] 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
patient is not improving rapidly on systemic corticosteroid of whom (25%) presented at least one relapse, characterized
monotherapy [52]. by cutaneous lesions. These flare-ups have been associated
with the viral reactivation of HHV-6 [47]. Nevertheless, a
4.4 Clinical Features more pronounced lymphocytosis, presence of mononucleo-
sis, and more severe hepatic cytolysis have been suggested
DReSS/DiHS presents with a combination of fever, diffuse to be a more important viral-dependent reaction in prolonged
rash, and signs of organ involvement [44] (Table 3), which DReSS/DiHS [62].
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 5 Differential Diagnosis
the onset of DReSS/DiHS of 3 weeks to 3 months [50].
Fever (38–40  °C) is the most common sign (seen in One of the most difficult differential diagnoses is SJS/
90–100% of cases), followed by a skin rash (87% of cases) TEN, which is a SCAR and clinically manifests with fever,
[53]. The skin rash usually involves more than half of the a skin eruption, and systemic symptoms. In SJS/TEN, the
body surface area and may even develop into erythroderma. onset of symptoms tends to appear between 3 and 21 days
The cutaneous lesions are frequently of polymorphic pres- after the patient has started the drug, which is a shorter
entation, described as maculopapular, urticarial, exfolia- period of time after the medication was initiated than in
tive, lichenoid, pustular, bullous, target-like, or eczema-like DReSS/DiHS. However, there is not a substantial differ-
lesions [54]. Facial edema has been reported as frequently as ence in this period of time, making it hard to differenti-
in 76% of cases, which constitutes a warning sign, because ate DReSS/DiHS from SJS/TEN [64]. Fortunately, there
in common cutaneous adverse drug reactions the face is usu- are distinguishing features that allow this differentiation.
ally spared [29, 55, 56]. Mucosal involvement, mainly of the For instance, SJS/TEN is characterized by the presence of
lips and oral cavity, can be present in 56% of cases [29, 57]. detachable skin while DReSS/DiHS presents as a morbil-
Different organs and systems can be affected during liform or maculopapular rash instead. DReSS/DiHS may
DReSS/DiHS. Hematological abnormalities are usually have some blisters as a consequence of the pressure of the
observed, eosinophilia being most common (95%), followed surrounding edema. In contrast to SJS/TEN, DReSS/DiHS
by neutrophilia (78%), monocytosis (69%), and atypical lym- histopathology does not show the epidermal necrosis com-
phocytes (67%); lymphadenopathy has been identified is as monly seen in SJS/TEN. In addition, the presence of eosin-
many as 54% of patients [29, 55, 58]. The most commonly ophilia and atypical lymphocytosis will support a DReSS/
affected organ is the liver (75–94%), followed by the kidneys DiHS diagnosis instead of SJS/TEN. Also, the multiple
(12–40%), lungs (one-third of cases), heart (4–27%), and organ involvement behaves differently between them. For
neurological system (headaches, seizures, coma, and motor instance, hepatitis and tubule interstitial nephritis are seen
function impairment) [59, 60]. in DReSS/DiHS, while liver and kidney injury manifests
As reported in the literature, eosinophilia, lymphadenopa- as increased liver enzymes and prerenal azotemia in SJS/
thy, fever, and liver injury have been significantly associated TEN. An overlap of DReSS/DiHS and SJS/TEN should
with a ‘probable/definitive’ case of DReSS/DiHS according be diagnosed when a case fulfills the criteria for a definite
to the RegiSCAR’s scoring system. The same study revealed or probable diagnosis of the two SCARs, according to the
that skin rash and liver damage are the most common clini- scoring systems. In 2012 a retrospective study reported
cal features associated with DReSS/DiHS, and eosinophilia a 2.1% prevalence of true overlap syndromes from 145
is the third most frequently reported sign in this condition confirmed SCAR cases. They found just three overlap-
[46]. ping SCARs, in which DReSS/DiHS was the common
Organ involvement, based on a clinical investiga- denominator; one case was a DReSS/DiHS/AGEP overlap
tion, including medical imaging, electroencephalogram and two cases were DReSS/DiHS and SJS/TEN overlaps
(EEG), biopsy, and blood work, is part of the criteria at the [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 regarding describing it as DReSS/DiHS with AGEP features
patients presents with fever, rash, and severe internal organ or a DReSS/DiHS/AGEP overlap [67].
involvement; this not only takes into account that SJS/TEN Mycosis fungoides and Sézary syndrome present with
has a poorer prognosis with a high mortality rate but also multiple scaly erythematous patches/plaques or general-
considers that the most important factor for mortality in ized erythroderma, respectively. Hepatosplenomegaly,
DReSS/DiHS is the development of TEN [66]. lymphadenopathies, and B cell symptoms may be present.
The two major fundamental differences between DReSS/ Sézary syndrome is characterized by neoplastic T cells in
DiHS and AGEP are the morphology of the skin lesions the skin and peripheral blood (at least 1000 cells/µL) and/
and the period of latency between the drug exposure and or increased CD4 + lymphocytes with a CD4/CD8 ratio ≥ 10
appearance of symptoms [46]. In contrast to DReSS/DiHS, in the peripheral blood, and a clonal TCR rearrangement in
AGEP presents with an abrupt onset of fever along with the the blood identified by polymerase chain reaction (PCR) or
appearance of multiple tiny sterile pustules disseminated all Southern blot analysis are present [68]. These skin disorders
over the skin surface that appear within the first 3 days of may have additional cutaneous manifestations such as pal-
drug exposure. If a delayed drug reaction fulfils criteria for moplantar hyperkeratosis, infiltrated plaques, and exophytic
both AGEP and DReSS/DiHS, we agree with other authors tumors.
DReSS: How Far Have We Come?

Another differential diagnosis is hypereosinophilic In summary, the few differences between the Japanese
syndrome, which manifests with marked eosinophilia validation criteria and the RegiSCAR criteria for DReSS/
(≥ 1500 cells/µL) and eosinophil-mediated multiple-organ DiHS are skin eruption developing after 3 weeks of exposure
damage, without the context of a drug exposure. The skin to a limited number of drugs and HHV-6 reactivation as
involvement may be seen as urticaria, eczema, or erythro- diagnostic criteria in the Japanese criteria; and skin biopsy,
derma [69]. resolution after at least or following 15 days, other organ
Adult-onset Still disease (AOSD) is a multisystem inflam- involvement besides the liver, and evaluation of other poten-
matory condition of unknown etiology [70]. It manifests tial causes as the RegiSCAR criteria.
clinically with spiking fevers, transient maculopapular rash,
lymphadenopathy, hepatosplenomegaly, polyarthralgia, 6.1 Causality Assessment
and sore throat. In complicated cases, patients may develop
pericarditis, hemophagocytic syndrome, and/or chronic Proper identification of the culprit drug is of utmost impor-
arthropathy [71]. Laboratory tests show an increase in ferri- tance not only to know to avoid them to prevent new epi-
tin, erythrocyte sedimentation rate (ESR), C-reactive protein sodes of DReSS/DiHS, but also correct identification of the
(CRP), and leukocytosis with a predominance of neutrophils causal medication helps identify drugs not related to these
[72]. Multiple diagnostic or classification criteria have been severe drug reactions and encourages the patient to continue
proposed, the Yamaguchi criteria being the most widely them.
accepted; however, AOSD is a diagnosis of exclusion [73]. Throughout the years, multiple methods for assessing
causality, including expert judgment or global introspec-
tion, operational algorithms, and probabilistic approaches,
6 Diagnosis have been designed [74]. In 1976, the Karch-Lasagna algo-
rithm was proposed as an assessment tool to pursue system-
DReSS/DiHS is a diagnosis sui generis; however, misdi- atic evaluation of an adverse drug reaction [75]. In 1980,
agnosis is common. In 1996, Bocquet et al. [17] proposed Naranjo and colleagues [76] designed a method for assess-
a diagnostic criteria comprising just three features: skin ing the probability of adverse drug reactions with a scored
eruption; eosinophilia ≥ 1.5 × 109/μL; and internal organ questionnaire of ten parameters, in which each question has
involvement signified by transaminase elevation ≥ 2 times three answer options: ‘Yes’, ‘No’, or ‘Do not know’ [76].
normal, lymphadenopathy > 2 cm in diameter, or nephritis, The results are categorized depending on the total score as
interstitial pneumonia, or carditis [17]. follows: definite if ≥ 9; probable if 5–8; possible if 1–4; and
In 2006, a Japanese group proposed a diagnostic score doubtful if ≤ 0. This scale was consensually validated by
that included the presence of HHV-6 reactivation as a crite- three experts, six raters, and by a good correlation found
rion [45, 50]. They found that HHV-6 IgG titers and DNA with another algorithm [77]. In 1982, Jones [78] described
usually are detected 2–3 weeks after onset of the rash. They an algorithm for adverse events validated by the FDA, which
suggested that HHV-6 reactivation might be a cause of is based on the assessment of four parameters: the temporal
hypersensitivity syndrome. The association between HHV-6 relationship within the drug and the adverse event, dechal-
reactivation and DReSS/DiHS has been described by several lenge, challenge, and evaluation of a confounding disease.
authors since 1997 [19–21]. Tohyama et al. reported two The Bayesian Adverse Reactions Diagnostic Instrument
DReSS/DiHS cases where HHV-6 antibodies were detected (BARDI), which assesses several serious adverse events,
more than 2 weeks after the onset of the disease and while including hypersensitivity skin reactions, has been used con-
the patients were in the hospital. They also reported the pres- sistently [79–82]. BARDI includes epidemiologic and clini-
ence of DNA on the skin biopsy in one patient [20]. cal data and gives a probability result between 0 (unlikely)
In 2007, the RegiSCAR group developed a scoring sys- and 1 (certainty) [83, 84]. Currently, with computational
tem for DReSS/DiHS diagnosis after a multinational study techniques, the Bayesian network is a tool that allows cau-
in Austria, France, Germany, Israel, Italy, and the Nether- sality assessment to be carried out in a pharmacovigilance
lands (Table 3). In this study, DReSS/DiHS was diagnosed center [82].
if the patient was hospitalized because of a suspected drug- Unfortunately, there is not a specific algorithm of cau-
related reaction, and at least three of the additional following sality of DReSS/DiHS as there is for SJS/TEN [85]. Inter-
criteria were met: acute skin rash, fever, lymphadenopathy estingly, the ALDEN (algorithm of drug causality for epi-
of at least two sites, an involvement of at least one inter- dermal necrolysis) algorithm takes the elimination half-life
nal organ, lymphocytosis or lymphocytopenia, peripheral value of the drugs into consideration to avoid the incorrect
eosinophilia, and thrombocytopenia. Based on this scoring impression that symptoms may not be secondary to a drug
system, patients were classified into definite, probable, pos- reaction if the drug has been withdrawn from the patient’s
sible, or no diagnosis of DReSS/DiHS [61]. medication regimen before the onset of the symptoms. For
S. A. Martínez-Cabriales et al.

instance, it is important to be aware that patients on allopuri- treatment [91, 101]. Unfortunately, there is not enough evi-
nol can develop symptoms 2 weeks after the drug is stopped dence regarding the influence of immunosuppressive drugs
because allopurinol and/or its metabolites are slowly cleared, on the outcome of the PT [102]. A randomized double-blind
especially if the patient has renal insufficiency. In addition, study found that 20 mg/day of oral prednisone suppressed
a systematic review of allopurinol-induced DReSS/DiHS PT reactivity in patients hypersensitive to nickel [103]. A
reported long periods of time between the clinical manifesta- prospective study reported positive PT reactions in patients
tions and the starting of the allopurinol, with 90% (489/538) on azathioprine, cyclosporine, mycophenolate mofetil, meth-
of the cases within 8.6 weeks (60 days) [86]. Another study otrexate, infliximab, adalimumab, etanercept, and tacroli-
reported a latency time of 25.7  weeks (or 180  days) in mus [102]. The ESCD guidelines recommend being aware
allopurinol-induced DReSS/DiHS [87]. of false-negative reactivity in patients on immunosuppres-
A study by Shear [88], which had an objective of organ- sive therapy and to postpone PT if possible [93]. Because
izing our initial thoughts on the topic, reported a stepwise of the lack of a well-standardized PT method, the sensitivity
approach to a suspected adverse reaction. In addition, and specificity are yet unknown. One study reported that the
Kardaun et al. [29] recommend a series of steps to exclud- positive predictive values were higher than the negative pre-
ing unlikely drugs: (a) drugs taken for more than 3 months; dictive values, and that they were high as 80–90% for certain
b) drugs stopped more than 2 weeks before the index day; drugs such as carbamazepine, but only around 10–20% for
and (c) drugs just initiated less than 3 days before the prob- other medications such as phenobarbital. These differences
able index day [29]. Afterward, an expert panel classified the were attributed to technical and toxicokinetic characteristics
suspected remaining drugs as ‘very probable,’ ‘probable,’ of the drugs [90, 104]. Two other studies reported positive
‘possible,’ and ‘undetermined’ according to the likelihood rates of PT of 64% (46/72) and 32.1% (18/56) using the
reported in the literature. same method described by the ESCD guidelines [105, 106].
In both studies, the lack of positive results to allopurinol
6.2 Patch Testing causing false-negative results was noticed. Barbaud et al.
[105] also reported negative PT results to salazopyrin in five
Patch testing (PT) is a safe in vivo test used to identify the patients. Interestingly, in this study there was a patient who
causative drug of a hypersensitivity syndrome [89]. This had a positive PT to carbamazepine and cloxacillin 11 years
method consists of applying the drug, previously diluted in a after his first PT, and multiple drug reactivity to different
media (petrolatum sp., water, or ethanol), on the skin, along classes of drugs was reported in 18% (13/72) of DReSS/
with the media alone used as a control [90]. It is recom- DiHS [105].
mended the commercialized form of the drug be tested, as
well as the pure active substance. Several guidelines for PT 6.3 Confirmation of Causality
relating to drug reactions recommend testing the commer-
cialized drug diluted at 30% and the pure substance at 10%, The lymphocyte transformation test (LTT) and the meas-
both in petrolatum sp. and water [91, 92]. The European urement of drug-specific IFN-γ-releasing cells by enzyme-
Society of Contact Dermatitis (ESCD) recommends using linked immunospot (ELISpot) assay are experimental meth-
the powder from intravenous preparations or capsules from ods that help to identify the culprit drug. These methods
the drugs used by the patients to prepare the in-house PT require specific expertise and are not part of the diagnostic
material into an active principle in a final 10% (wt/wt) dilu- routine. In an international consensus of in vitro methods
tion [93]. On the other hand, as other authors have reported for the diagnosis of drug hypersensitivity reactions by the
drug reaction symptoms occurring after PT to aciclovir, car- European Network on Drug Allergy (ENDA) and European
bamazepine, or pseudoephedrine, they recommend starting Academy of Allergy and Clinical Immunology (EAACI), a
the first dilution of the drug at 0.1% and, if negative, increas- grade C recommendation was given to each of these methods
ing it up to 10% [94–96]. [107].
PT should be performed on the sites that were previously
affected. Several reported cases showed negative results 6.4 Lymphocyte Transformation Test
from PT when they were applied on the back, but positive
results in the same patients when the tests were performed The LTT is an in vitro standard laboratory method that helps
on the most highly affected cutaneous sites [91, 97, 98]. to identify the culprit drug in drug-induced hypersensitivity
According to the International Contact Dermatitis Research reactions. This test measures the T cell proliferation, specifi-
Group (ICDRG), a test looking for a local reaction should cally the H-thymidine, in response to a drug after incuba-
be read at 48 and 96 h and, if negative, on day 7 [93, 99, tion [108]. The advantage of the LTT over PT is that can
100]. PT should be performed during the 6 months follow- detect drug reactions caused not only by a delayed hyper-
ing DReSS/DiHS and 1 month after any immunosuppressive sensitivity but also by other immunopathologic mechanisms;
DReSS: How Far Have We Come?

however, the combination of both tests is best to determine of lymphocytes CD8 + , cytotoxic granzyme B + lympho-
the causative drug. The appropriate time to perform the LTT cytes, Forkhead box P3 + (FOXP3+) Tregs, plasma cells,
is 4–8 weeks after remission in order to elude high prolif- eosinophils, and neutrophils are usually present. Eosinophils
eration of spontaneous cells [109]. There have been cases are not expected to be present in all cases, even in patients
that obtained positive results even 10 years later; however, who have peripheral eosinophilia. Atypical lymphocytes
it is also known that some cases will lose reactivity within with hyperchromatic nuclei have been described in different
4 years. Because its sensitivity is in the range of 60–73%, series [123]; however, a genetic clonal mutation has not been
a negative result cannot rule out a drug hypersensitivity found [120]. Other common histologic findings are dermal
syndrome [108, 110, 111]. On the other hand, this test has edema, dilated blood vessels, and extravasated erythrocytes.
specificity rates of at least 85% [108, 111]. Vasculitis is not a feature; however, nuclear debris has been
observed in some biopsies [120].
6.4.1 Drug-Specific Interferon-γ-Releasing Cells by ELISpot A study reported that the presence of several inflamma-
Assay tory patterns in a single biopsy is a clue pointing towards
DReSS/DiHS [120], the most common being the association
In a study by Takahashi et al. [49] an expansion of functional of the eczematous and interface patterns (20%), followed by
Tregs was found in the acute stage of DReSS/DiHS [49]. the association of interface dermatitis and erythema multi-
In their investigation, they reported an increase in IFN-γ forme-like dermatitis (14%), and, finally, the least common
and TNF-α in peripheral blood mononuclear cells (PBMCs) was the combination of interface dermatitis, eczematous
when stimulated with relevant drug Ag in vitro. They then dermatitis, and AGEP-like histopathology [120]. Another
analyzed the effect of depletion of Tregs on cytokine pro- histologic pattern recently described by Chiou et al. [119]
duction by drug Ag-specific effector cells. In this scenario, is the pseudolymphoma pattern, which consists of large
a dramatic increase in IFN-γ and TNF-α was documented lymphoid cells with hyperchromatic nuclei in the epider-
under basal or Ag-stimulated conditions, but only during the mis, upper dermis, and around superficial dermal vessels.
acute stage. This demonstrated the importance of Tregs in Clinic pathological correlation has been reported between
cytokine production. the epidermal necrosis and liver damage as well as renal
The IFN-γ ELISpot assay is an in vitro technique that disease [120, 124].
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 7 Management
lymphocytes to proliferate and release IFN-γ, which will be
detected by the ELISpot assay [112]. This method has been Initial management of DReSS/DiHS requires a withdrawal
proposed for used in the acute phase of the hypersensitiv- of the culprit drug, replacement of intravenous fluids, cor-
ity when is urgent to determine the culprit drug [113]. One rection of acid–base and electrolyte disturbances, a hyper-
study showed a significant correlation between this method caloric diet, and a multidisciplinary evaluation. Additional
and LTT (r = 0.65, p < 0.01) [114]. Another study reported management includes preventing and/or treating any bacte-
a significant correlation between these two methods in rial superinfection and providing adequate skin care.
patients with a history of β-lactam-induced maculopapular Corticosteroids remain the mainstay treatment for this
rash [115]. Klaewsongkram et al. [116] reported that this condition. Several reported case series and cases have docu-
method was immunogen specific for allopurinol in allopu- mented their efficacy; however, no clinical trials have sup-
rinol-induced SCAR patients and showed a sensitivity and ported either corticosteroids or other therapies in DReSS/
specificity of 79% and 95%, respectively [116]. DiHS (Table 5). A study suggested that topical corticoster-
oids alone may be considered for the management of milder
6.5 Histopathology forms of DReSS/DiHS based on fewer relapses and fewer
in hospital days in these patients in comparison to those on
DReSS/DiHS histopathology is variable [117–120]. It is systemic corticosteroids; however, a death was seen in this
described as spongiotic dermatitis and as an exanthematous group [125]. Uhara et al. [126] reported a case series of ten
drug reaction that commonly has eosinophils and apoptotic DReSS/DiHS patients treated without systemic corticoster-
keratinocytes [118, 121, 122]. The histologic features seen at oids who experienced full recovery after 7–37 days without
the epidermis are orthokeratosis, parakeratosis, acanthosis, systemic complications. Three received topical corticoster-
spongiosis, and lymphocyte exocytosis. Subcorneal pustules oids along with hydration, and the rest received only hydra-
have also been described [120] and vacuolization of the basal tion. Two more patients were included in the study, but one
layer involving the adnexae is commonly seen. At the der- dose of 40 mg of dexamethasone and prednisolone treatment
mis, band-like and/or perivascular inflammatory infiltrates 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) Pts Treatments Mortality (%) Cause of death

Chiou et al. (Taiwan, 2008) [119] 30 (M: 15; F: 15) SS (IV hydrocortisone initially and changed to oral 10 Supportive therapy: 1 died from staphylococcal
prednisone): 22 (76%) pts pneumonia with septic shock; 1 died from upper
Oral antihistamines and supportive therapy: 7 (24%) gastrointestinal tract bleeding
pts SS: 1 died due to an acute renal failure secondary to
TS: 30 pts rhabdomyolysis
Mansur et al. (Turkey, 2008) [178] 31 (M: 15; F: 16) SS (methylprednisolone 32–80 mg/day): 27 pts 3 6 (19.4%) pts developed a blister dermatitis: 3 SJS and
TS + antihistamines: 3 pts 3 TEN
1 TEN pt died of sepsis
Eshki et al. (France, 2009) [127] 15 (M: 5; F: 10) SS: 10 (67%) pts 20 SS: 1 died from myocarditis, hepatitis, and pneumonitis
IVIG in addition to corticosteroid therapy: 3 (20%) SS + IVIG: 1 died from multi-organ failure; 1 died due
pts to hemophagocytosis, rhabdomyolysis, encephalitis,
Liver transplant: 1 (6.7%) pt infection, and pancytopenia
Ben m’rad et al. (France, 2009) [70] 24 (M: 12; F: 12) SS: 11 pts (Prednisone 0.3–1 mg/kg/day tapered over 0
4–12 months)
Chen et al. (Taiwan, 2010) [28] 60 (M: 26; F: 34) SS (IV methylprednisone 40–120 mg/day or oral 10 SS: 1 died due to multi-organ failure, 1 due to cardio-
prednisolone 30–60 mg/day): 45 pts (75%) genic shock, and 1 due to shock with negative blood
IVIG: 2 pts in addition to corticosteroids (1 recovered cultures
and 1 died) SS + antibiotics: 1 died due to septic shock
Antibiotics: 6 pts SS + IVIG + antibiotics: septic shock
Supportive care + antihistamines: 10 pts Antibiotics alone: 1 died from septic shock
Um et al. (Korea, 2010) [171] 38 (M: 18; F: 20) SS: 16 pts (42.1%) 2.6 SS: 1 died from an opportunistic infection + liver fail-
TS + antihistamines: 22 (57.9%) pts with complete ure; 1 pt had liver damage but was lost to follow-up
recovery Complete recovery was noted in 36 pts (94.8%)
Ang et al. (Singapore, 2010) [179] 27 (M: 12; F: 15) SS (IV or oral): 25 (92.6%) pts of whom 17 had oral 0
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
Wongkitisophon et al. (Thailand, 2012) [174] 27 (M: 14; F: 13) SS (IV dexamethasone 15–20 mg/day or oral predni- 3.7 1 pt died from multi-organ failure and sepsisa
solone 0.5–0.7 mg/kg/day): 23 (85.2%) pts
Supportive therapy: 4 pts (corticosteroids were
avoided due to HIV infection)
Sultan et al. (India, 2014) [180] 17 (M: 8; F: 9) SS: 17 pts (dexamethasone IV equivalent to pred- 5.9 1 died from hepatic failure
nisolone 1–1.5 mg/kg/day until the rash and fever
disappeared, then oral prednisolone)
Funck-Brentano et al. (France, 2015) [125] 38 (M: 19; F: 19) SS: 13 pts (methylprednisolone: 10; oral prednisone: 2.63 TS: 1 died due to hypovolemic shock a few weeks after
3) he was discharged
TS: 25 (66%) pts
Avancini et al. (Brazil, 2015) [181] 27 (M: 17; F: 10) SS: oral prednisone 1 mg/kg/day in all pts; 3 pts 4 1 died from hepatic failure
required dose to be increased to 1.5 mg/kg/day and
1 was switched to IV methylprednisolone)
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] 25 (M: 11; F: 14) SS (IV or oral): 13 (52%) pts 12 3 pts died:
SS + IVIG: 2 pts IV SS: 1 died due to renal failure
TS + antihistamines: 12 (48%) pts TS + antihistamines: 1 had pneumonia with septic
shock; 1 died because of septic shock
Matta et al. (Mexico, 2017) [184] 11 (M: 4; F: 7) SS: 8 pts (oral prednisone 0.5–1 mg/kg) 9 SS: 1 died due to sepsis secondary to pneumonia
Antihistamines: 1 pt
Not specified for the other 2 pts
Ichai et al. (France, 2017) [185] 16 (M: 5; F: 11) NAC: all pts. Loading dose: 50 mg/kg in 1 h then 25 SS: 5 pts improved. The other 4 pts either died or had
50 mg/kg in 4 h, then 100 mg/kg/day liver transplant
SS: 9 pts (2 received oral prednisolone 1 mg/kg/ 1 died from multi-organ failurea; 1 died on the waiting
day and 7 received 500 mg × 3 days), of whom 5 list for a liver transplanta
improved and 4 worsened After liver transplant: 1 died due to a systemic fungal
Liver transplant: 5 pts 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
S. A. Martínez-Cabriales et al.

In cases with severe organ involvement, systemic cor- higher after treatment with systemic corticosteroids than
ticosteroid therapy could achieve clinically and laboratory after topical treatment [p = 0.06]; increased viral loads of
improvement within a few days; however, in some cases HHV-6 and CMV have been reported during corticosteroid
corticosteroid therapy is not effective or even allows the treatment [132]), which might be associated with long-last-
disease to flare when the dose is tapered [127]. The recom- ing and relapsing corticosteroid-dependent DReSS/DiHS,
mended dose is 1 mg/kg/day gradually tapered over at least the French Society of Dermatology proposed valganciclovir
3 months [128, 129]. The duration of the therapy depends use in combination with systemic corticosteroids for those
on the clinical evolution of the patient as well as laboratory patients with the presence of severity signs and confirmed
test results. Although it is not needed for most cases, a slow major viral reactivation of HHV-6 [128]. It may be helpful
taper over 3–12 months to avoid flares may be necessary for in minimizing complications related to HHV-6 reactiva-
some severe clinical presentations [70]. tion. Asano et al. [133] reported one patient who worsened
The French Society of Dermatology proposed the follow- on corticosteroids and IVIG and died due to hemorrhagic
ing treatment algorithm: shock caused by gastrointestinal bleeding associated with
CMV enterocolitis 34 days after intravenous ganciclovir
(a) In the absence of severity signs, the patient can be man- 200 mg/day was added. In another case where the patient
aged symptomatically with topical corticosteroid emol- had received IVIG as a single treatment because of their
lients and H1 antihistamines. medical history of hepatitis C virus infection, the patient
(b) In the presence of signs of severity (transaminases showed improvement in cutaneous ulcers and gastrointes-
levels > 5 times normal; pneumonia, heart and/or tinal bleeding 2 weeks after starting ganciclovir 200 mg/
kidney involvement; and hemophagocytosis), treat- day [133].
ment includes systemic corticosteroids equivalent to Unfortunately, there is little evidence regarding alter-
1 mg/kg/day of prednisone with a multidisciplinary native treatments for DReSS/DiHS. Case series and case
approach. reports have reported cyclosporine, IVIG, mycophenolate
(c) In a life-threatening context such as hemophagocytosis mofetil, cyclophosphamide, and rituximab as beneficial
with bone marrow failure, encephalitis, severe hepati- therapeutic options [134]. A case series of two patients
tis, renal failure, and respiratory failure, systemic cor- reported a rapid and successful response to short courses
ticosteroids are recommended with intravenous immu- of 3–7 days of cyclosporine (3 days of 5 mg/kg/day and
noglobulin (IVIG) at a dose of 2 g/kg over 5 days. IVIG 7 days of 200 mg/day) as a first-line therapy [135]. Other
should not be administered in the absence of corticos- authors have reported the use of cyclosporine in unrespon-
teroids. sive cases to long courses of oral corticosteroids. One sub-
(d) In those cases with the presence of severity signs and ject with phenytoin DReSS/DiHS was treated with systemic
confirmation of a major viral reactivation (HHV-6), corticosteroids over 9 months and ultimately responded after
systemic corticosteroids plus antiviral medications 6 months of cyclosporine 4 mg/kg/day [136]. A patient with
(e.g., ganciclovir) with or without IVIG is recom- DReSS/DiHS due to vancomycin who had not improved
mended [128]. on 2 weeks of corticosteroids achieved improvement after
5 days of cyclosporine 100 mg twice daily [137]. A compli-
Methylprednisolone 30 mg/kg intravenously for 3 days cated recurrent DReSS/DiHS with eosinophilic polymyositis
could be administered as an alternative option to oral cor- requiring mechanical ventilatory support previously treated
ticosteroids. One case series reported a short recovery of with oral corticosteroids finally responded after combination
7–8 days after the use of one pulse of methylprednisolone in therapy of intravenous cyclosporine 100 mg/day, methyl-
pediatric patients [130]. A pilot study of ten DReSS/DiHS prednisolone 60 mg/day, and three IVIG cycles of 1 g/kg/day
syndromes treated with pulsed intravenous methylpredni- for 2 days [138]. Lastly, the patient received an additional
solone 500 mg daily for three consecutive days followed by IVIG infusion and was prescribed azathioprine with medium
a 30-day tapering course of oral prednisone starting with doses of prednisone, which continued for almost a year until
30 mg and tapering 10 mg every tenth day reported a rapid all laboratory tests were normalized.
response to methylprednisolone with a good clinical out- On the other hand, fatal outcomes have been reported with
come but one death after failure of a liver transplant and two cyclosporine. A case of sulfasalazine-induced DReSS/DiHS
short-term complications: corticosteroid-induced psychosis with recalcitrant rash was reported that failed to respond to
on day 31 of corticosteroids and type 1 diabetes mellitus on systemic corticosteroids and cyclosporine and then devel-
day 25 of treatment. The other seven patients did not showed oped into eosinophilic myocarditis, resulting in the death
sequelae during the period of observation of 1–4 years [131]. of the patient 6 weeks after starting the culprit drug [139].
Considering the use of systemic corticosteroids could pro- A similar case was reported in a trimethoprim–sulfameth-
mote viral reactivation (viral reactivation was significantly oxazole-associated DReSS/DiHS that deteriorated into an
DReSS: How Far Have We Come?

eosinophilic myocarditis, causing the death of the patient unsuccessfully treated with 1 month of intravenous and oral
even after combination therapy with IVIG, cyclosporine, and corticosteroids. One pulse of 750 mg/m2 of intravenous
systemic corticosteroids [134, 140]. cyclophosphamide was given and 11 days later was switched
IVIG has immunomodulatory and anti-inflammatory to 100 mg/day orally for 6 months, when full recovery was
effects. The former therapeutic effect seems to be due to achieved [150]. In DReSS/DiHS complicated with severe
the presence of antivirus IgG in the IVIG batch, which respiratory distress and myocarditis that required mechani-
could work against herpes virus reactivation, including that cal ventilatory support and cardiovascular reanimation, a
of HHV-6 [141–143]. Several authors support the use of response was seen 12 h after the first of four plasmapheresis
high doses of IVIG as an adjuvant treatment to corticoster- sessions, which were performed every other day along with
oids. The recommended dose for IVIG is 1 g/kg for 2 days systemic corticosteroids [151].
or 2 g/kg over 5 days [128]. A case has been reported of One case has been reported of a beneficial response in the
lamotrigine-induced DReSS/DiHS that had flared twice skin rash and liver involvement of N-acetylcysteine (10 g
when prednisone was tapered down to 10 mg which was intravenously followed by 2.5 g every 6 h for the next 3 days)
finally successful treated after 4 months of IVIG (0.5 g/kg/ as a first-line therapy in a sulfasalazine DReSS/DiHS that
day for 2 days) as an adjuvant therapy [144]. Three cases was previously diagnosed as acetaminophen toxicity. When
have reported a successful outcome with IVIG as mono- DReSS/DiHS was diagnosed, prednisone along with valgan-
therapy [143, 145, 146]. However, a prospective study does ciclovir was added for 3 months. The authors suggest that
not support IVIG as a single treatment. This study included N-acetylcysteine might work by limiting the drug-derived
six patients who received 200 mg/kg/day for five consecutive reactive metabolites [152]. However, its beneficial effect was
days. Only one patient achieved a complete response; the not demonstrated in another sulfasalazine DReSS/DiHS case
other patients developed a severe adverse effect to the IVIG. [153]. N-acetylcysteine efficacy was also reported in an anti-
There were two hemophagocytic syndromes, two cases of convulsant-induced DReSS/DiHS [154], but a case series
malaise that required stopping the IVIG infusion, and one reported angioedema as an adverse effect in three patients
pulmonary embolus. In the end, oral corticosteroids were 2–3 days after intravenous N-acetylcysteine (2 g four times
given to two patients with hemophagocytic syndrome and to daily) was administered and when the skin rash associated
two uncontrolled allopurinol-induced DReSS/DiHS patients with DReSS/DiHS had already been resolved [155].
[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 8 Prognosis
effects. Also, it is controversial whether giving these thera-
pies increases the frequency of autoimmune sequelae. Higher risk of severe organ involvement has been reported
Mycophenolate mofetil 500 mg twice daily was effec- in allopurinol- and minocycline-induced DReSS/DiHS
tively used as a corticosteroid-sparing agent in a DReSS/ cases when compared with other drugs [127, 156]. Vis-
DiHS in a 14-year-old female [148]. Another case reported ceral involvement comprising multi-organ failure seems
the efficacy of mycophenolate mofetil as an adjuvant ther- to be unpredictable. HHV-6 reactivation, pancytopenia,
apy to IVIG and systemic corticosteroids in a sulfasalazine- hypereosinophilia > 1500 cells/µL, heart rate > 90 beats/
induced DReSS/DiHS that had failed to respond to 4 months min, white blood cells > 12,000/mm3, respiratory rate > 20
of corticosteroid monotherapy and developed into eosino- breaths/min, coagulopathy, gastrointestinal bleeding, and
philic myocarditis. The patient required a left ventricular systemic inflammatory response syndrome are indicators of
assist device for 53 days and received maintenance therapy poor prognosis [28, 47, 70, 119, 157]. Hepatic dysfunction
with mycophenolate mofetil along with lower doses of pred- appears in 51–87% of cases, and is the most common cause
nisone for 1 year [140]. A 4-day course of plasmapheresis of death [119, 127, 156, 158]. Heart involvement could
and rituximab demonstrated efficacy in a minocycline- appear even months after DReSS/DiHS and could turn into
induced DReSS/DiHS with eosinophilic myocarditis in a a fulminant myocarditis [134, 140].
patient who was previously unsuccessfully treated with a Infectious diseases including herpes simplex, herpes zos-
high dose of corticosteroids, mycophenolate, and cyclo- ter, CMV, Pneumocystis jirovecii, and cryptococcal pneu-
sporine [149]. For maintenance, the patient was put on a monia have been reported most commonly within 3 months
weekly rituximab infusion over a month and continued on after DReSS/DiHS. A study reported two cases of CMV
prednisone 15 mg/day and mycophenolate mofetil 1500 mg reactivation thrombotic infarction that occurred within
twice daily [149]. 2 months after DReSS/DiHS [159]. One case was chrono-
Cyclophosphamide showed an effective response in an logically associated with a large deep venous thrombosis
ibuprofen-related DReSS/DiHS with severe kidney fail- in the inferior cava vein and bilateral femoral veins [160].
ure, acute myocarditis, and eye involvement that had been Herpes zoster has been reported to appear between 2 months
S. A. Martínez-Cabriales et al.

and 3 years after the onset of DReSS/DiHS [132, 161]. Kano DiHS [159]. Multiple autoimmune sequelae have been seen
et al. [161] reported a herpes zoster prevalence of 11% (3/28) in the same patients [169]. Brown et al. [162] reported an
in a 6-month observation period after DReSS/DiHS, in autoimmune thyroiditis, type 1 diabetes, elevated ANA, and
which two cases appeared during the tapering of the cor- anti-Smith and anti–Sjögren syndrome-A (SS-A/Ro) anti-
ticosteroid dose [161]. Interestingly, a retrospective study body titers after a minocycline-induced DReSS/DiHS [162].
of 34 DReSS/DiHS cases, in which 14 patients received In terms of prognosis, it is unknown whether systemic
corticosteroid treatment, reported that most viral infections corticosteroids improve the survival of DReSS/DiHS
(herpes zoster, encephalitis, and CMV) were detected when patients. Regarding sequelae, one study documented a dif-
the oral corticosteroid dose was decreased to 25–67% of the ferent effect of systemic corticosteroids on short-term (less
initial dose [132]. P. jirovecii pneumonia (2.5 months after) than 6 months after DReSS/DiHS) and long-term outcomes
and cryptococcal pneumonia (2.5 months after) were seen of DReSS/DiHS. In the short-term outcome, corticoster-
when the corticosteroid dose was reduced to 50% and 15% oids were associated with multiple infections, but in the
of the initial dose, respectively [132]. long-term outcomes, those patients treated with corticos-
Although most patients will achieve complete recov- teroids (0.6–1.0 mg/kg daily tapered mostly over 8 weeks)
ery after withdrawal of the culprit drug, close monitoring documented an absence of autoimmune disease, while lupus
including blood work is required because frequent flar- erythematosus and autoimmune thyroiditis, along with the
ing, late organ involvement, and long-term sequelae may presence of autoantibodies after complete resolution of the
lead to end-organ failure or autoimmune diseases such as DReSS/DiHS, was seen in those patients who did not receive
hyperthyroidism, hypothyroidism, type 1 diabetes, systemic corticosteroids [132, 159]. The presence of autoimmune
lupus erythematosus (SLE), autoimmune hemolytic anemia, sequelae might be explained by the decrease in the suppres-
and sclerodermoid graft-versus-host disease-like lesions sive function of the Tregs in the resolution phase of DReSS/
[119, 132, 144, 162–165]. Autoimmune diseases following DiHS, allowing a higher risk of developing an autoimmune
DReSS/DiHS are related to viral infection or reactivation disease [49].
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 9 Conclusion
defined as the onset of clearly diagnosed diseases, devel-
opment of end-organ failure after resolution of drug DReSS/DiHS develops in the setting of a complex interac-
hypersensitivity, or the onset of disease during the acute tion of genetic, viral, and environmental factors. Although
stage that was not resolved after DReSS/DiHS [168]. The there are still some questions to be answered regarding
study reported Graves’ disease 36  days and 8.7  months DReSS/DiHS and its physiopathology, the disease is now
after DReSS/DiHS in two young patients; alopecia areata well-characterized. The RegiSCAR score allows identifica-
2 years after the DReSS/DiHS; fulminant type 1 diabetes tion of potential cases and classifies them in order to avoid
(FT1DM) 48 days after the DReSS/DiHS; hemolytic ane- missing real DReSS/DiHS cases. However, concern has
mia 14 days after the DReSS/DiHS in a patient with SLE; emerged regarding cases being reported as DReSS/DiHS
and two patients with underlying hypertension, diabetes, without organ involvement because they scored 4 points on
and chronic renal insufficiency who developed deteriora- RegiSCAR. For instance, a patient may present with derma-
tion of their renal function requiring lifetime hemodialy- titis, swollen lymph nodes, and high levels of eosinophilia;
sis 10 days and 2.7 years after DReSS/DiHS [168]. Kano however, these findings can be observed in severe atopic
et al. reported autoimmune thyroid disease as being the dermatitis as well. Identifying the disease is imperative to
most common sequelae of DReSS/DiHS in 4.8% (7/145) of remove the culprit drug and address potentially fatal com-
cases, followed by FT1DM in 3.45% (5/145) [159]. The time plications. Those patients without severe organ involvement
interval between DReSS/DiHS and thyroid autoimmune dis- may be treated with topical corticosteroids and supportive
ease—Graves’ disease, Hashimoto thyroiditis, and painless care; however, monitoring of the course of the disease must
thyroiditis—is 2 months to 3 years [162, 168]. The FT1DM be done and if liver, kidney, lung, or other organ injury
appeared within 2 months (mean of 42 days) of onset of develops, systemic corticosteroids should be initiated until
DReSS/DiHS. Other complications were one case each of clinical and laboratory normalization, followed by a slow
vitiligo (4.5 months after), rheumatoid arthritis (10 years taper over 3 months. Regarding the benefit of corticoster-
after), lupus erythematosus with severe lupus nephritis oid treatment in mortality, there is not enough evidence to
(4 years after DReSS/DiHS in a patient who received IVIG allow us to reach specific conclusions, and further studies
alone) [165], and thrombotic infarction (2 months after) are required. However, corticosteroids remain the mainstay
[159]. Two patients with underlying renal disease required treatment option in severe cases based on the long-term evi-
lifetime hemodialysis, starting 1 and 5 years after DReSS/ dence of retrospective studies and case series reported in
DReSS: How Far Have We Come?

the literature. After recovery, the patient should be educated 15. Shear NH, Spielberg SP. An in vitro lymphocytotoxicity assay
regarding the culprit drug and there should be long-term for studying adverse reactions to sulphonamides. Br J Derma-
tol. 1985;113(Suppl 28):112–3.
follow-up for identification of possible autoimmune com- 16. Shear NH, Spielberg SP. Pharmacogenetics and adverse drug
plications. In cases where there is a defined genetic risk, reactions in the skin. Pediatr Dermatol. 1983;1(2):165–73.
patients should be tested and encouraged to share that infor- 17. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolym-
mation and its relevance with close family members such as phoma and drug hypersensitivity syndrome (Drug Rash with
Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan
children and siblings. Med Surg. 1996;15(4):250–7.
Lastly, we consider the term DReSS/DiHS to be the most 18. Sontheimer RD, Houpt KR. DIDMOHS: a proposed consensus
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zine associated with reactivation of human herpesvirus 6. Arch
Funding No funding was received for the preparation of this review. Dermatol. 1998;134(9):1113–7.
21. Suzuki Y, Inagi R, Aono T, Yamanishi K, Shiohara T. Human
Conflict of interest S.A. Martinez-Cabriales, F. Rodriguez-Bolaños, herpesvirus 6 infection as a risk factor for the development of
and N.F. Shear declare that they have no conflicts of interest. severe drug-induced hypersensitivity syndrome. Arch Dermatol.
1998;134(9):1108–12.
22. Shiohara T, Kano Y, Takahashi R, Ishida T, Mizukawa Y. Drug-
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