DERMATOLOGICA SINICA 31 (2013) 196e204

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Dermatologica Sinica
journal homepage: http://www.derm-sinica.com

REVIEW ARTICLE

Drug reaction with eosinophilia and systemic symptoms:

A drug-induced hypersensitivity syndrome with variable
clinical features
Yi-Chun Chen 1, Yung-Tsu Cho 2, Chia-Ying Chang 2, Chia-Yu Chu 2, *
1
Department of Dermatology, Cathay General Hospital, Taipei, Taiwan
2
Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity
Received: Jul 6, 2013 syndrome (DIHS) involves a unique and severe adverse drug reaction. Patients present with fever, rash,
Revised: Sep 15, 2013 lymphadenopathy, hematological abnormalities, systemic illness, and may suffer from prolonged cour-
Accepted: Sep 24, 2013
ses. Although the precise pathogenesis of DRESS/DIHS is not fully understood, it is widely considered to
be an immunological reaction to a drug or drug metabolites. In this review article, we discuss the his-
Keywords:
torical aspects of nosology, variable clinical and histopathological features, advantages and disadvantages
allopurinol
of using an international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) and Japanese DIHS
autoimmune diseases
eosinophilia
criteria, pathogenesis, treatment, and long-term sequelae of DRESS/DIHS. Early recognition of this syn-
hypersensitivity drome, withdrawal of suspected culprit drugs, and adequate supportive care are mainstays of improving
StevenseJohnson syndrome patient prognosis and reducing morbidities and mortality. Moreover, some DRESS/DIHS patients may
develop long-term sequelae, especially autoimmune diseases and end organ failure. Physicians should be
aware of these possibilities in patients after DRESS/DIHS and cautiously follow-up symptoms and lab-
oratory tests for early detection of these sequelae.
Copyright Ó 2013, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. All rights reserved.

Introduction gradually decreased. Recently, another SCAR has begun to attract

attention due to its unique clinical features and unknown patho-
Adverse reactions to drug therapies are a concern for all medical genesis: drug reaction with eosinophilia and systemic symptoms
personnel and also for the general public. Drug complications are (DRESS); its description reflects the typical presentation of rash,
the most common type of adverse event during hospitalization1 hematologic abnormalities, and systemic illness.
and the skin is one of the organs most often affected. According This peculiar syndrome was first reported in the literature in
to the literature, cutaneous adverse drug reactions affect 2e3% of 1937, where it was described as exfoliative dermatitis following
hospitalized patients.2,3 Fortunately, most of these reactions pre- administration of sulfanilamide.6 Until 1950, systemic complica-
sent as benign maculopapular exanthema or urticaria.3 However, tions of this drug hypersensitivity, such as lymphadenopathy and
severe cutaneous adverse reactions (SCARs) affect about 1 of every visceral involvement, had been widely reported.7 After this, an
1000 inpatients.4 increasing number of patients presenting with similar but variable
SCARs to drugs are groups of idiosyncratic hypersensitivity re- manifestations received diagnoses defined by the drugs that caused
actions with a heterogeneous clinical presentation.5 Two of the the reaction, including phenytoin hypersensitivity,8 dapsone hy-
most notorious SCARs are StevenseJohnson syndrome (SJS) and persensitivity (sulfone syndrome),9 allopurinol hypersensitivity
toxic epidermal necrolysis (TEN) due to their rapid progression and syndrome,10 and anticonvulsant hypersensitivity syndrome.11
high morbidity/mortality rates. With extensive reporting and bet- Because lymphadenopathy was commonly reported in these pa-
ter education of physicians and patients, the incidence of both has tients, the term “drug-induced pseudolymphoma” was once
confusedly used to describe such condition12 but then was super-
seded by “drug-induced hypersensitivity syndrome” (DIHS) to
* Corresponding author. Department of Dermatology, National Taiwan University differentiate its acute systemic symptoms from pseudolym-
Hospital and National Taiwan University College of Medicine, Number 7, Chung-Shan
phoma.13 These systemic hypersensitivity syndromes were
South Road, Taipei, Taiwan.
E-mail address: [email protected] (C.-Y. Chu). renamed as “drug rash with eosinophilia and systemic symptoms”

1027-8117/$ e see front matter Copyright Ó 2013, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.dsi.2013.09.006
 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204 197

in 1996,14 but drug “reaction” was later used because of the varia- Although the cardiac complications are rare, these can easily lead
tion of cutaneous involvement. to death. Thus, physicians should be alert for such clinical
Even now, the underlying mechanisms of DRESS/DIHS are only symptoms.
partially understood and many issues about this controversial en- Neurologic symptoms, such as headache, seizure, coma, or
tity are still being debated. In this article, we will re-examine this disturbed speech are all usually reported, as signs of meningitis and
severe drug eruption and add new information to help clarify some encephalitis. Hippocampal involvement points to a diagnosis of
unrevealed topics about DRESS/DIHS. limbic encephalitis and syndrome of inappropriate secretion of
antidiuretic hormone has been reported in DRESS/DIHS patients.26
Clinical presentation and pathological findings HHV-6 encephalitis associated with drug hypersensitivity syn-
drome has been described but not necessarily always detected.27
Clinical symptoms and laboratory findings Hypersensitivity syndrome may also results in acute pancrea-
titis,28 arthritis,29 or gastrointestinal bleeding.30 The severity of
DRESS/DIHS symptoms typically occur 2e6 weeks14 after drug organ involvement can vary from subclinical to fatal or can only be
intake; however, reactions may not develop until 3 months later, recognized months or years later after the development of such
especially when the syndrome is induced by allopurinol.15 A high, organ failures.17
spiking fever (usually >38
C) and rash are usually the first signs, Various hematologic abnormalities have been described in pa-
and these are followed by other systemic reactions such as cervical, tients with DRESS/DIHS. Atypical lymphocytes and/or eosinophilia
axillary and inguinal lymphadenopathy, arthritis, or general mal- is the most prominent and characteristic sign22; in our previous
aise. The rash begins as a nonspecific morbilliform eruption study, the incidence was 63% and 52%, respectively.15 Other ab-
(Figure 1A), which is indistinguishable from other less severe drug normalities include leukocytosis or leukopenia, thrombocytopenia,
reactions, but can progress to a generalized form or even to and hypogammaglobulinemia in the early stages.31 Most hemato-
erythroderma (Figure 1B). Facial and acral edema with periorbital logic changes return to normal without causing significant
accentuation is an evocative sign for the diagnosis (Figure 1C) and morbidity. However, the presence of pancytopenia is significant
may induce blister formation due to severe dermal edema.14 The because it predicts a poor prognosis,15 and hemophagocytic syn-
cutaneous eruption later becomes confluent and infiltrated drome developing during the course of DRESS/DIHS may be an
(Figure 1D) with purpuric changes, especially when it affects the underlying cause that is easily overlooked.
lower extremities (Figure 1E). As the rash resolves, the end stage
involves large sheet desquamation (Figure 1F). Occasionally, Pathological findings
pinhead-sized pustules (Figure 1G) and atypical target lesions
(Figure 1H) may also be observed. Mucosal regions can be involved No single pathological finding is specific enough to make a diag-
in DRESS/DIHS but in such cases, the symptom is usually mild, and nosis of DRESS/DIHS; however, the results of skin biopsy will help
seen as cheilitis (Figure 1I) or erythematous pharynx rather than as rule out other diseases, such as lymphoma or hematological and
extensive erosions seen in SJS/TEN.16,17 infectious disorders.32 In most cases, diffuse or superficial peri-
Multiple organ involvement is another distinct feature of vascular lymphocytic infiltration is the most frequently observed
DRESS/DIHS but the actual incidence varies. The liver and kidney feature on dermatopathological slides. One or more reactive pat-
are the two most frequently involved organs, and the incidence terns may accompany this inflammatory background, including
ranges from 50% to 87% and 10% to 53%, respectively.4,18,19 Anicteric epidermal spongiosis (Figure 2A), basal cell vacuolization with the
hepatitis presenting as elevated serum alanine aminotransferase is presence of some dyskeratotic cells (Figure 2B and C), and promi-
more common in patients with DRESS/DIHS, but when it becomes nent endothelium (Figure 2D), possibly with red blood cell
icteric, this usually signals a poorer prognosis.20 Most patients extravasation.33 Eosinophils and dermal edema may also be present
recover from hepatitis without specific targeted management, but (Figure 2E). Severe perivascular lymphocytic infiltration may be
acute liver failure may develop and can contribute to patient accompanied by endothelial damage and, in rare cases, by red blood
mortality if liver transplantation is unsuccessful. In addition, cell extravasation presenting as lymphocytic vasculitis (Figure 2F).
recurrent elevation of liver enzymes, with or without relapsing Earlier reports pointed to a band-like infiltrate of atypical lym-
fever and rash, may correlate with reactivation of human herpes- phocytes with epidermotropism observed on the skin biopsy.14
virus 6 (HHV-6).21 However, we believe that the presence of atypical lymphocytes is
Renal involvement usually presents with increased serum not a prominent feature, so that DRESS/DIHS can be differentiated
creatinine levels and new-onset proteinuria. In our previous study, from lymphoma and pseudolymphoma. Moreover, recent serial
chronic renal insufficiency and allopurinol-induced DRESS/DIHS case studies have established that interface dermatitis with either a
increased the risk of renal involvement.15 In addition, interstitial vacuolar or lichenoid pattern indicative of basal cell degeneration is
nephritis, rather than tubular necrosis, was the more common another common feature of this severe drug reaction.15,19
cause of acute renal failure in DRESS/DIHS patients. The severity of
renal dysfunction varies from a mild increase in serum creatinine Unique presentation of DRESS in Taiwan
levels to the development of end-stage renal disease.
Although the incidence is lower, other visceral organs can be The clinical manifestation of DRESS/DIHS is heterogeneous. Study
involved during DRESS/DIHS. Pulmonary involvement presents as series conducted in different geographic areas also display some
nonproductive cough or breathlessness, which may be complicated individual and unique features, possibly reflecting the difference in
by acute interstitial pneumonitis, pleuritis, or adult respiratory ethnicity or in medical care systems (Table 1).15,18,21,33 In Taiwan,
distress syndrome.22 Cardiac and muscular complications include the most common cause can be traced to allopurinol. This finding
myocarditis,23 rhabdomyolysis,24 and atrioventricular block.25 The may be associated with higher prevalence of HLA-B*5801 in Han
diagnosis of DRESS/DIHS-induced myocarditis usually depends on Chinese and more prescription of allopurinol for asymptomatic
clinical symptoms (chest pain, unexplained tachycardia, hypoten- hyperuricemia in Taiwan. In addition, the prevalence of end-stage
sion), electrocardiogram changes (diffuse ST-T changes), and some renal disease in Taiwan ranked second in the world from 2002 to
nonspecific changes on echocardiograms (reduction in ejection 2005.34 We believe all these factors make allopurinol the leading
fraction) and chest radiographs (cardiomegaly, pleural effusion).22 culprit for DRESS/DIHS in Taiwan, and further result in a high renal
198 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204

Figure 1 Clinical presentations of DRESS/DIHS. (A) The skin rash of DRESS usually begins as a nonspecific morbilliform eruption, which is indistinguishable from other less severe
drug reactions, but it can then progress to (B) a generalized infiltrated form or even to exfoliative dermatitis (erythroderma). (C) Typical skin lesions for DRESS are facial edema, (D)
confluent and infiltrated plaques, (E) purpuric change, and (F) psoriasiform desquamation as a late stage manifestation. (G) Pin-head sized pustules and (H) atypical target lesions
may also be observed. (I) Mucosal regions can be involved in DRESS/DIHS but are usually mild as cheilitis.

involvement rate.15 However, although the prevalence of hepatitis Diagnostic criteria and differential diagnosis
B virus infection (HBV) is high in Taiwan,35 the hepatic involvement
rate in Taiwan DRESS patients did not absolutely exceed that of Because of the diverse cutaneous presentation and variable sys-
other countries. Besides, we found that DRESS/DIHS patients with temic involvement, diagnosing DRESS/DIHS is often challenging. In
HBV or HCV infection did not tend to have hepatic involvement.15 fact, even within the past decade, the existence of this “syndrome”
This indicates that chronic HBV or HCV infection may not be a was still being debated. However, discussion and worldwide
risk factor for liver involvement. Fortunately, most patients recov- research efforts have helped identify additional characteristics to
ered from hepatic injury spontaneously, and death from hepatic improve diagnosis. Most experts agree that DRESS/DIHS has some
failure is seldom reported in Taiwan. special features, including delayed onset and prolonged courses,
 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204 199

Figure 2 Pathologic features of DRESS include (A) epidermal spongiosis, (B) some dyskeratotic cells, interface dermatitis with either a vacuolar or lichenoid pattern indicating (C)
basal cell degeneration, and (D) prominent endothelium, possibly with red blood cell extravasation. (E) Eosinophils and dermal edema may be present. (F) Diffuse or superficial
perivascular lymphocytic infiltration is frequently observed, which may be accompanied by endothelial damage and, in rare cases, by red blood cell extravasation presenting as
lymphocytic vasculitis.

frequent multiple organ involvement, and sequential HHV reac- system should be applied to diagnose an included case as DRESS,
tivation. Better isolation and clarification of this hypersensitivity depending on individual final scores (Table 2). The strength of the
syndrome also helps physicians manage these patients and predict RegiSCAR criteria lies in selecting patients with a varied phenotype
their clinical course and prognosis. Prior to making the diagnosis of and making an attempt to exclude other conditions that mimic
DRESS/DIHS, clinicians should always rule out other conditions, DRESS. Disadvantages include the need for hospitalization and a
especially infection or autoimmune diseases. In order to establish lengthy process involving many laboratory tests that are not always
the correct diagnosis, patients’ symptoms, along with many readily available. Some cases might be falsely validated as noncases
asymptomatic signs, should be carefully surveyed. because of inadequate information. Application of these criteria
may be limited in a hospital-based setting or used only in expert
Diagnostic criteria meetings.37 Moreover, people who are not familiar with criteria in
the RegiSCAR DRESS scoring system may overestimate the value
Although there is still no universal consensus about the definition and misclassify no/possible cases to probable/definite cases.
of DRESS/DIHS, two diagnostic criteria are mainly adopted. The Therefore, detailed information about how to apply the RegiSCAR
international Registry of Severe Cutaneous Adverse Reactions DRESS scoring system is provided in Table 2.
(RegiSCAR) group has suggested a series of inclusion criteria for By contrast, the Japanese consensus group established another
suspicious DRESS cases, in which hospitalized patients with a re- set of criteria, with the inclusion of HHV-6 reactivation as a diag-
action suspected to be drug related must have at least three of the nostic criterion for DIHS (Table 3).38 If all criteria are present,
following systemic features: acute skin rash; fever above 38
C; especially evidence of HHV-6 reactivation, the diagnosis of typical
enlarged lymph nodes; internal organ involvement; and hemato- DIHS is made; otherwise, atypical DIHS is diagnosed when the first
logical abnormalities, including lymphocytosis or lymphocytope- five criteria are present. Compared to the RegiSCAR criteria, the
nia, eosinophilia, and thrombocytopenia.36 Furthermore, a scoring Japanese criteria are more easily applied by general physicians or

Table 1 Comparison of clinical features of drug reaction with eosinophilia and systemic symptoms in different studies.

Clinical features Peyrière et al/ France18 Tohyama et al/ Japan21 Chen et al/ Taiwan15 Walsh et al/ UK33

Top three common Aromatic anticonvulsants, Aromatic anticonvulsants, Allopurinol, aromatic Aromatic anticonvulsants, minocycline,
culprit drugs abacavir, nevirapine allopurinol, mexiletine anticonvulsants, dapsone sulfasalazine
Fevera 69 90 87 100
Skin eruption Morbilliform exanthem Morbilliform exanthem Morbilliform exanthem, indurated Urticated papules, morbilliform
papules and plaques exanthem, EM-like lesions
Lymphadenopathya 18 54 31 88
Eosinophiliaa 57 57 52 93
Atypical lymphocytesa 7 75 63 NA
Hepatic involvementa 52 34 80 100
Renal involvementa 10 NA 40 7
Mortalitya 10e40 5 10 11

Data are presented as %.

EM ¼ erythema multiforme; NA ¼ not available.
a
Incidence.
200 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204

Table 2 Scoring system of RegiSCAR for diagnosing drug reaction with eosinophilia and systemic symptoms (DRESS).

Assessment/ Score 1 0 1 Comment

Fever  38.5
C No/U Yes Acute episodes

Enlarged lymph nodes No/U Yes >1 cm, 2 different areas (right side plus left side is not adequate)
Eosinophilia No/U Yes Score 2 for extreme eosinophilia
Eosinophils  0.7  109/L or  Eosinophils  1.5  109/L or
10% if leukocyte < 4.0  109/L  20% if leukocyte < 4.0  109/L
Atypical lymphocytes No/U Yes
Skin rash Onset < 21 days prior to hospitalization
Extent >50% body surface area No/U Yes
Rash suggesting DRESS No U Yes 2 symptoms: purpuric changes (other than legs), facial edema, infiltration,
psoriasiform desquamation
Biopsy suggesting DRESS No Yes/U Score e1 if results fit any other specific dermatopathologic diagnosis
Organ involvement Excluding other causes, score maximum of 2
Liver: any 1 criterion No/U Yes  ALT > 2  UNL, twice on successive dates
 D-bil > 2  UNL, twice on successive dates
 AST, T-bil, ALP all >2  UNL, once
Kidney: any 1 criterion No/U Yes  Creatinine > 1.5  patient’s baseline, twice on successive dates
 Proteinuria > 1 g/day, hematuria, decreased creatinine clearance or decreased GFR
Lung: any 1 criterion No/U Yes  Evidence of interstitial lung (CT, x-ray)
 Abnormal bronchoalveolar lavage fluid or biopsy specimen
 Abnormal blood gases
Muscle/Heart: any 1 criterion No/U Yes  Raised serum CPK > 2  UNL
 Raised isoenzyme fractions: CPK-MM (skeletal muscle), CPK-MB (heart muscle)
 Raised troponin T (>0.01 mg/L)
 Abnormal imagings, including chest x-ray, echocardiogram, ECG, EMG, CT, or MRI
Pancreas No/U Yes Amylase and/or lipase > 2  UNL
Other organs No/U Yes Spleen, thyroid gland, central nervous system, gastrointestinal tract
Rash resolution  15 days No/U Yes
Excluding other causes No/U Yes Score 1 if 3 tests are performed and negative
Hepatitis A, B, C At least 2 tests are negative and 1 U: negative
Mycoplasma/chlamydia At least 1 test is negative and 1 U: negative
Antinuclear antibody
Blood culture Sampling within 3 days of index date
Final Score

Final scores: <2: excluded; 2e3: possible; 4e5: probable; > 5: definite. EBV/CMV and HHV6/7 are also recorded; results, however, do not influence the score.
ALP ¼ alkaline phosphatase; ALT ¼ alanine transaminase; AST ¼ aspartate transaminase; CMV ¼ cytomegalovirus; CPK ¼ creatine phosphokinase; CPK-MB ¼ creatine
phosphokinase-muscle/brain type; CPK-MM ¼ creatine phosphokinase-muscle type; CT ¼ computed tomography; D-bil ¼ direct bilirubin; DRESS ¼ drug reaction with
eosinophilia and systemic symptoms; EBV ¼ EpsteineBarr virus; ECG ¼ electrocardiogram; EMG ¼ electromyogram; GFR ¼ glomerular filtration rate; HHV ¼ human
herpesvirus; MRI ¼ magnetic resonance image; T-bil ¼ total bilirubin; U ¼ unknown; UNL ¼ upper normal limit.

dermatologists working in local clinics because the suggested lab- reaction is getting longer, not just with limited drugs. Another
oratory tests are easily available, and those tests need not be important issue is the discrepancy in viewing HHV reactivation
repeated. However, some probable cases may not fulfill the diag- between different study groups. Evidence of HHV-6 reactivation is
nostic criteria set by the Japanese consensus group because not all included as a critical criterion to diagnosing typical DIHS for the
well-known symptoms or signs will be present in all patients. In Japanese consensus, but is not enrolled in the scoring system pro-
addition, the list of drugs associated with such hypersensitivity posed by RegiSCAR group. This may explain the higher HHV-6
reactivation rate for DRESS/DIHS patients in Japanese studies
(62%),21 compared to that in other studies adopting RegiSCAR
Table 3 Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) criteria (45%),39 and also may help support our view of taking DIHS
established by the Japanese group.38,a as a more typical DRESS. However, the definite role of viral reac-
1. Maculopapular rash developing > 3 weeks after starting with a limited tivation in DRESS/DIHS is still debatable, and it has still not been
number of drugsb conclusively explained whether the reactivation of HHV-6 and
2. Prolonged clinical symptoms 2 weeks after discontinuation of the causative other members of the HHV family are part of the disease itself or
drug
3. Fever > 38
C
whether they are better interpreted as a complication of this
4. Liver abnormalities (alanine aminotransferase > 100 U/L)c syndrome.
5. Leukocyte abnormalities (at least one present)
a. Leukocytosis (>11  109/L)
b. Atypical lymphocytosis (>5%) Differential diagnosis
c. Eosinophilia (>1.5  109/L)
6. Lymphadenopathy
7. Human herpesvirus 6 reactivation
The skin rash seen in DRESS/DIHS may be highly variable and dy-
namic as the disease progresses or fluctuates. When cutaneous
Note: From “The diagnosis of a DRESS syndrome has been sufficiently established on
manifestation is the first symptom, a diagnosis of maculopapular
the basis of typical clinical features and viral reactivations,” by T. Shiohara, M. Iijima,
Z. Ikezawa, and K. Hashimoto, 2007, Br J Dermatol, 156, p.1083e1084. Copyright exanthem is often presumed. When patients have discernible
2007, John Wiley and Sons. Adapted with permission. pustules or bullous lesions, acute generalized exanthematous
a
The diagnosis is confirmed by the presence of all seven criteria (typical DIHS) or pustulosis (AGEP), SJS/TEN, and generalized bullous fixed drug
the presence of five criteria (1e5, atypical DIHS) eruption (GBFDE) should be considered in the differential diag-
b
Limited number of drugs for the majority of cases in Japan includes the
following eight: carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine,
nosis.40 However, the onset of skin eruption is usually delayed, and
dapsone, salazosulfapyridine, and allopurinol neither extensive epidermal necrolysis nor subcorneal pustules are
c
This can be replaced by other organ involvement, such as renal involvement. a prominent feature of DRESS/DIHS,32 except in rare cases
 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204 201

presenting overlaps between DRESS and other SCARs.41 Along with results. The optimal time for performing this test is 2e6 months
the development of fever, lymphadenopathy, or atypical lympho- after the initiation of drug reaction.45
cytosis, acute viral infection should be considered. Primary human The lymphocyte transformation test (LTT) mainly focuses on
immunodeficiency virus, EpsteineBarr virus (EBV) infection, and detecting drug-specific T-cells by measuring the proliferation of T-
reactivation of HHV-6 can all present as mononucleosis-like illness cells after encountering the antigens. The specificity of LTT is
with rash and systemic symptoms.16 When the liver is involved, evaluated to be 85%,46 but the sensitivity is also variable and is
hepatotropic viruses, such as hepatitis viruses, and even pandemic related to both the drug and phenotype of clinical reactions.47 For
influenza infection should be carefully investigated. Viral serolog- b-lactam-delayed-type allergy, the sensitivity rate of LTT was re-
ical tests usually help but correct timing of sampling or repeating ported to be in the range of 60e70%.48 However, well-documented
tests is important to optimize their benefit. data are lacking for other drugs tested by LTT. Other limitations of
Depending on induration and purpuric changes observed in skin the LTT include its high laboratory test cost, as well as advanced
lesions, cutaneous T-cell lymphoma or other hematological disorders techniques that demand experience and careful interpretation for
and systemic vasculitis should be carefully ruled out. In addition, reliable results. Nevertheless, LTT should be considered in patch-
some DRESS patients may eventually progress to erythroderma, test-negative patients because overall sensitivity is higher than
which makes correct diagnosis more challenging. Vasculitis with other tests detecting delayed type hypersensitivity. The optimal
multiple organ involvement can mimic systemic drug hypersensi- time to perform LTT is still being debated, but for DRESS patients,
tivity. ChurgeStrauss syndrome should be taken into account, espe- 5e8 weeks after acute episodes has been suggested.49
cially when patients also present with systemic eosinophilia. Other
vasculitic diseases to be differentiated include Wegener’s gran-
Pathogenesis
ulomatosis, polyarteritis nodosa, and even systemic lupus
erythematosus.
The precise pathogenesis of DRESS/DIHS is complex and not fully
Histopathological tests may help to identify the pattern and size
understood. It is widely considered to be an immunological reac-
of involved vessels and a serological examination to establish an
tion to a drug or to its metabolites because of the signs, such as skin
autoimmune profile is also essential when such conditions are
eruption, fever, and reappearance of symptoms upon readminis-
strongly suspected. If patients experience rapid deterioration to
tration of the drug. However, exposure to associated drugs does not
erythroderma, a history of pre-existing skin disorders such as
seem to be enough to develop DRESS/DIHS. Increasing results of
eczema or psoriasis should be sought. Sézary syndrome or other
pharmacogenetic studies are showing that the occurrence of this
lymphoma/leukemia is not easily distinguishable from a drug
syndrome is determined by the combination of susceptible in-
eruption. Histologically, atypical lymphocytes with epidermotrop-
dividuals and exposure to specific drugs. However, the mechanisms
ism or aberrant intradermal distribution are characteristic. Other-
underlying the flaring of symptoms of DRESS/DIHS cannot be
wise, immunohistochemical staining and establishing cell clonality
explained solely by an immunological reaction to drugs. The link
in the blood can aid in the diagnosis for lymphoma/leukemia.16
between DRESS/DIHS and HHV-6 reactivation has evoked much
interest in recent years. Some authors consider HHV-6 reactivation
Diagnostic tools for DRESS/DIHS
a consequence of immunosuppression, either due to drug hyper-
sensitivity or to immunosuppressive treatment17; others view this
Determining the culprit drug for DRESS/DIHS patients is critical but
as the early event.39 Recently, gradual dysfunction of regulatory T-
sometimes difficult. Patients might take several medications just
cells was reported and was speculated to be associated with
before or during their adverse drug reactions. An additional factor
increasing risks of developing autoimmune diseases.50
that makes it difficult to find the true drug causing the reaction is
the characteristic delayed onset of symptoms in DRESS/DIHS.
Although drug provocation testing may serve as the gold standard Immunological hypersensitivity reaction
to establish the diagnosis of drug hypersensitivity, this is not
appropriate for SCARs patients because of the potential life- DRESS/DIHS only occurs in a relatively small proportion of patients
threatening risks. Patch testing and the lymphocyte trans- and thus is an idiosyncratic hypersensitivity reaction. This syn-
formation test are two clinical tests that may benefit these patients. drome is classified as type IV or delayed type hypersensitivity
Patch testing has been widely used for diagnosing type IV or because of the need for an incubation period for sensitization.
delayed type hypersensitivity. A drug patch test is performed by Activated T-cells seem to play a central role in such hypersensi-
applying a diluted drug in suitable media on the skin, to detect tivity. Some have further claimed that DRESS/DIHS has a dominant
inflammatory effects by drug-specific T-cells. Although it is a safe type IVb reaction, which corresponds to the Th2-type immune
test, several factors are known to affect its sensitivity and speci- response and eosinophil activation.51 Studies have demonstrated
ficity. Prior to when patch testing is ordered for DRESS/DIHS pa- the existence of drug-specific T-cells in patients with drug hyper-
tients, the physician should evaluate some important factors, sensitivity and expansion of these T-cells when encountering spe-
including the drug category to be tested, drug concentration and cific antigens.52 However, their effector roles in DRESS/DIHS are still
vehicle used, and timing of the test after drug hypersensitivity. elusive. Drugs associated with these reactions may covalently bind
Overall positive rates for DRESS patch tests are diverse, ranging protein or DNA to form hapten-carrier complexes (hapten theory)
from 32.1% to 64%.42,43 However, some similar results have been or may directly interact with immune receptors on T-cells (p-i
repeatedly verified. In the case of anticonvulsants, studies reported concept) to stimulate the immune cells.53 The interaction between
to have a 51.5% positive rate; especially for carbamazepine, the human leukocyte antigen (HLA), drugs, and T-cell receptors (TCR) is
positive rate rose to more than 70%.42e44 Other drugs reported to pivotal to such a T-cell-mediated response. When a drug or
produce positive patch tests include b-lactam antibiotics, proton metabolite interacts with a particular HLA, and if drug presentation
pump inhibitors, and some non-steroidal anti-inflammatory to naïve T cells via the TCR stimulates their activation, immune
drugs.42,43 By contrast, patch tests always yield negative results in responses are initiated. Individuals possessing specific HLA are
allopurinol-induced DRESS/DIHS. In a systemic review of anticon- predisposed to developing DRESS/DIHS after sensitization by
vulsant hypersensitivity syndrome, performing patch tests during particular drugs; however, these allelic markers are possibly
or right after hypersensitivity episodes yielded low rates of positive necessary but not sufficient to evoke such allergic reactions
202 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204

because of their high negative predictive values but low positive central role in initiating this drug hypersensitivity reaction when
predictive values.54 the drugs and specific HLA alleles accidentally activate viral specific
Scientists first found the correlation between HLA and drugs T-cells.68 Other researchers have demonstrated EBV replication in
early in the 21st century. In published data, abacavir-hypersensitive patients’ EBV-transformed B lymphocytes after triggering by culprit
patients carried the allele HLA-B*5701 more frequently than drugs. These researchers claimed that symptoms of DRESS are
abacavir-tolerant patients did (odds ratio: 117; 95% confidence in- mediated by activated CD8þ T-cells whose targets in fact are her-
terval 29-481).55 Further studies have demonstrated this correla- pesviruses.39 However, more evidence is needed to clarify the
tion in Caucasian and Hispanic patients,56 but not in African and interaction between drugs, HHV, and host immune responses in
Asian populations.57 An international randomized pharmacoge- DRESS/DIHS patients.
netic clinical trial proved that avoidance of abacavir use in patients
with allele HLA-B*5701 reduced the incidence of this hypersensi- Regulatory T-cells
tivity syndrome, which was initially seen in 5% of patients receiving
this drug during the first weeks of treatment.58 Recently, the Recently, the roles of regulatory T-cells (Treg) have been studied in
mechanism of T-cell activation by abacavir was explained. Un- DRESS/DIHS patients, and their dynamic changes applied to explain
modified abacavir binds noncovalently to antigen-binding cleft of some of the mysterious problems of this drug hypersensitivity re-
HLA-B*5701 and subsequently changes its shape and chemistry, action. It was observed that Treg cells expanded during acute stages
along with changes to the peptide repertoire of HLA-B*5701. This but gradually lost their function during resolution phases of DRESS/
repertoire change alters the “immunological self”, after which DIHS.50 This led to the theory that expanded Treg cells with full
loading of novel self-peptides into altered HLA may drive T-cell capacities suppress activation of effector T-cells. This is reflected as
immune responses.59,60 This finding may also partially explain the a delayed onset of manifestations of DRESS/DIHS but also para-
occasional occurrence of drug-induced autoimmunity.60 Another doxically facilitates viral reactivation. Exhausted Treg cells become
well-known association is HLA-B*5801 and allopurinol-induced dysfunctional, which may partially explain why patients with
severe drug hypersensitivity reactions. This correlation was first DRESS/DIHS have an increased risk of developing autoimmune
reported in a case-controlled study of a Han-Chinese population. diseases in the future.68
One-hundred percent of patients diagnosed with allopurinol-
induced SJS/TEN and DRESS/DIHS carried the allele HLA-B*5801, Treatment and disease outcome
compared to only 15% in allopurinol-tolerant controls and 20% in
healthy controls.61 Similar strong associations were also demon- The only consensus about DRESS/DIHS patient treatment is to
strated in other Southeast Asian populations,62 Japanese pop- withdraw the offending drugs as soon as possible, along with
ulations,63 and also European patients64; this was most marked in providing adequate supportive care. Otherwise, it is still inconclu-
allopurinol-induced SJS/TEN. Although the mechanism of interac- sive what treatment benefits DRESS/DIHS patients. Empirical use of
tion between specific drugs and HLA variants is still not totally antibiotics or anti-inflammatory medications should be avoided to
understood, in many countries screening for these alleles is rec- prevent confusion between true deterioration due to newly
ommended prior to initiating therapy with these drugs. SCAR administered drugs or paradoxical deterioration of clinical symp-
occurrence may be partially preventable in the future. toms after withdrawal of causative drugs.
Topical corticosteroids can be used to relieve cutaneous symp-
Viral reactivation toms but the risk of superficial infection should always be kept in
mind. Systemic corticosteroids are the current mainstay of treat-
The association between this drug eruption and HHV was first re- ment. A recommended starting dose is 1.0e1.5 mg/kg/day of
ported in a patient with phenobarbital-induced hypersensitivity prednisone or an equivalent drug. This dosage should be slowly
syndrome.65 In that study, the authors reported that the antibody tapered over 6e8 weeks to avoid a flare-up of symptoms.17 How-
titer of HHV-6 rose during the 2nde4th week after the initiation of ever, studies focusing on indications and timing of administration
symptoms and this episode of viral infection was claimed to be and the influence of these factors on long-term outcomes for
related to the fulminant hemophagocytic syndrome developing in DRESS/DIHS patients are lacking. Because some patients may
that patient. Since then, continual evidence supports that viral completely recover without the need for systemic corticosteroids, it
reactivation might be a unique feature in such drug reaction and might be unnecessary to give systemic corticosteroids immediately
typical DIHS was proposed to imply its association with viral to all patients suspected of having DRESS/DIHS.69
reactivation.38 Other alternatives include intravenous immunoglobulin, plas-
Recently, reactivation of other types of herpesviruses was also mapheresis, or immunosuppressants; however, reports in the
discovered through different laboratory modalities; however, the literature have shown variable outcomes and inconclusive
mechanism for sequential viral reactivation and their pathogenetic results.70,71
roles in DRESS/DIHS are still unclear. Decreased B-lymphocyte The estimated mortality from DRESS/DIHS is 10e40%, accord-
numbers and total immunoglobulin levels were reported in a com- ing to different studies (Table 1), and the causes for death include
parison of patients with DRESS/DIHS and patients with SJS/TEN.66 In hepatic necrosis, shock, pulmonary hemorrhage, or other vital
addition, reduction of plasmacytoid dendritic cells (pDC) in the pe- organ decompensation.15,33 Years after the acute stage, patients
ripheral circulation was noted, and the authors speculated that this may have long-term sequelae, comprising newly developed
depressed the antiviral activity in DRESS/DIHS patients because autoimmune diseases and permanent visceral organ failure. In our
pDCs induce B cell maturation to produce immunoglobulin.67 previous study, the overall cumulative incidence of long-term
The role antiviral T-cells play in DRESS/DIHS is still being sequelae for DRESS/DIHS patients was 11.5%. Autoimmune thy-
debated. It has been proposed that T-cells specific to drugs and roid diseases and renal failure requiring long-term hemodialysis
viruses may have significant cross-reactivity in these patients, so were the most frequent sequelae for young patients and the
the clinical symptoms during acute episodes and after drug with- elderly, respectively.72 Variable autoimmune diseases were re-
drawal are partially induced by antiviral T-cells, which are stimu- ported in the literature, and there were occasional reports of in-
lated by bystander activation.17 Another scenario proposes that dividual patients developing more than one particular disease,
antiviral CD8þ T-cells possessing cross-reactivity to drugs play a either simultaneously or sequentially.22,73 The pathomechanism
 Y.-C. Chen et al. / Dermatologica Sinica 31 (2013) 196e204 203

of developing autoimmune diseases in DRESS/DIHS patients 16. Bachot N, Roujeau JC. Differential diagnosis of severe cutaneous drug eruptions.
Am J Clin Dermatol 2003;4:561e72.
possibly involves repeated stimulation of T-cells with autoreactive
17. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS):
potentials by sequential viral reactivation and dysfunction of a reaction induced by a complex interplay among herpesviruses and antiviral
regulatory T cells at resolution stages.74 However, autoimmune and antidrug immune responses. Allergol Int 2006;55:1e8.
diseases after DRESS/DIHS are variable, and they may involve both 18. Peyrière H, Dereure O, Breton H, et al. Variability in the clinical pattern of
cutaneous side-effects of drugs with systemic symptoms: does a DRESS syn-
autoantibody production (for example, autoimmune thyroid dis- drome really exist? Br J Dermatol 2006;155:422e8.
eases or systemic lupus erythematosus) and cell-mediated 19. Chiou CC, Yang LC, Hung SI, et al. Clinicopathological features and prognosis of
mechanisms (for example, alopecia areata or sclerodermoid le- drug rash with eosinophilia and systemic symptoms: a study of 30 cases in
Taiwan. J Eur Acad Dermatol Venereol 2008;22:1044e9.
sions). These are indications that immune regulation imbalance is 20. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern
multidimensional rather than having a single clear pathogenic Med 1995;155:2285e90.
process. Physicians should be aware of autoimmune generation in 21. Tohyama M, Hashimoto K, Yasukawa M, et al. Association of human herpes-
virus 6 reactivation with the flaring and severity of drug-induced hypersen-
patients after DRESS/DIHS and cautiously follow up symptoms sitivity syndrome. Br J Dermatol 2007;157:934e40.
and laboratory tests for early recognition. For elderly patients, 22. Kano Y, Ishida T, Hirahara K, Shiohara T. Visceral involvements and long-term
physicians should keep in mind that vital organ failure may lead to sequelae in drug-induced hypersensitivity syndrome. Med Clin North Am
2010;94:743e59.
death, which can occur either at the acute stage of the disease or 23. Shaughnessy KK, Bouchard SM, Mohr MR, Herre JM, Salkey KS. Minocy-
during the resolution stage of disease.72 cline-induced drug reaction with eosinophilia and systemic symptoms
(DRESS) syndrome with persistent myocarditis. J Am Acad Dermatol
2010;62:315e8.
Conclusion 24. Engel JN, Mellul VG, Goodman DB. Phenytoin hypersensitivity: a case of severe
acute rhabdomyolysis. Am J Med 1986;81:928e30.
DRESS/DIHS is a severe adverse drug reaction with unique clinical 25. Zhu KJ, He FT, Jin N, Lou JX, Cheng H. Complete atrioventricular block associ-
ated with dapsone therapy: a rare complication of dapsone-induced hyper-
features and complex pathomechanisms. Early recognition, with- sensitivity syndrome. J Clin Pharm Ther 2009;34:489e92.
drawal of possible causative drugs, and adequate supportive care 26. Sakuma K, Kano Y, Fukuhara M, Shiohara T. Syndrome of inappropriate
are mainstays of improving patient prognosis and reduce morbid- secretion of antidiuretic hormone associated with limbic encephalitis in a
patient with drug-induced hypersensitivity syndrome. Clin Exp Dermatol
ities/mortality. Most patients suffering from DRESS/DIHS recover 2008;33:287e90.
completely, but some may develop long-term sequelae, especially 27. Fujino Y, Nakajima M, Inoue H, Kusuhara T, Yamada T. Human herpesvirus 6
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771e4.
education and follow-up are necessary, and the search should 28. Descamps V, Mahe E, Houhou N, et al. Drug-induced hypersensitivity syn-
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This work was supported by the National Science Council of Taiwan 30. Asano Y, Kagawa H, Kano Y, Shiohara T. Cytomegalovirus disease during se-
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(NSC 99-2628-B-002 -084 -MY3) and National Taiwan University with drug-induced hypersensitivity syndrome. Arch Dermatol 2009;145:
Hospital (NTUH 102-S2058). 1030e6.
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