Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

DRESS syndrome: a detailed insight

Sapan Kumar Behera, Saibal Das, Alphienes Stanley Xavier & Sandhiya
Selvarajan

To cite this article: Sapan Kumar Behera, Saibal Das, Alphienes Stanley Xavier &
Sandhiya Selvarajan (2018): DRESS syndrome: a detailed insight, Hospital Practice, DOI:
10.1080/21548331.2018.1451205

To link to this article: https://doi.org/10.1080/21548331.2018.1451205

Accepted author version posted online: 08

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Publisher: Taylor & Francis

Journal: Hospital Practice

DOI: 10.1080/21548331.2018.1451205

DRESS syndrome: a detailed insight

Sapan Kumar Behera1, Saibal Das1, Alphienes Stanley Xavier1, Sandhiya Selvarajan1*

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1
Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical

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Education and Research (JIPMER), Puducherry, India

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Running head: DRESS Syndrome: A Detailed Insight
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*
Corresponding author:
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Name: Dr. Sandhiya Selvarajan

Address: Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate

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Medical Education and Research (JIPMER), Puducherry: 605 006, India

Email ID: sandhiyaselvarajan@gmail.com

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Tel No.: +919443492922

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Abstract:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious and

potentially fatal adverse effect to therapeutic medications. The incidence of this condition

varies among different ethnicities because of the difference in the genetic makeup. Though

fever, rash and eosinophilia are essential features for the diagnosis of this syndrome, these

vary from patient to patient along with the involvement of various organs such as liver,

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kidney, lungs, pancreas, etc. Some of the atypical features are dysphagia, agranulocytosis,

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and chylous ascites. Phenytoin, phenobarbitone, carbamazepine, and allopurinol are the most

common drugs responsible for developing this syndrome, although the list is fairly long.

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Among the criteria used for the diagnosis of DRESS syndrome, European Registry of Severe

Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR)

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criteria is the most commonly used one. The management of this syndrome involves early
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removal of the causative agent and treatment with anti-histamines and emollients in the mild

form, corticosteroids in the moderate form and plasmapheresis in the severe form along with
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other alternatives drugs. Healthcare professionals should be more vigilant about the early

manifestations of this syndrome, as early diagnosis and treatment improve outcomes

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considerably.
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Keywords: Corticosteroids, drug reaction with eosinophilia and systemic symptoms

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(DRESS), hypersensitivity, immune-allergic reaction, genetic predispositions viral

reactivation

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 1. Introduction:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare

hypersensitivity reaction, which is serious and potentially fatal. It is classified among severe

cutaneous adverse reactions (SCARs) with other cutaneous adverse drug, such as, Stevens-

Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized

exanthematous pustulosis (AGEP) [1]. The syndrome not only affects skin, but also other

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organs, such as, liver, kidney and heart. So the letter ‘R’ in the acronym DRESS previously

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stood for ‘rash’ was later changed to ‘reaction’ [2]. This syndrome was first recognized and

named as drug-induced hypersensitivity syndrome (DIHS) by Chaiken et al. in 1950, in a

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patient treated with phenytoin [3]. The other acronym used for DRESS syndrome is drug-

induced delayed multi-organ hypersensitivity syndrome (DIDMOHS) [3].

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2. Epidemiology:

The incidence of this syndrome is in the range of 1 in 1000 to 1 in 10,000 [4]. The overall
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mortality rate of this syndrome is 10-20% [5]. The incidence rate varies with drugs, for e.g., it

is2.3-4.5 per 10,000 and 1-4.1 per 10,000 for phenytoin and carbamazepine respectively [6].
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3. Pathogenesis:

The pathogenic factors causing DRESS syndrome are not clearly understood. But it has been
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hypothesized that the pathogenesis involves intricate interplay of following discussed factors

[7,8].

3.1.Genetic factors:

The variation of the incidence of DRESS syndrome across families and ethnicities may

suggest a significant role for genetics [9]. It has been found that DRESS syndrome is

associated with certain human leukocyte antigens (HLAs), such as, HLA-B*1502, HLA-

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B*1508, HLA-B*5701 and HLA-B*5801 [10–12]. Immune-allergic reactions to medications

are most commonly explained on the basis of hapten/pro-hapten hypothesis [13]. According

to this theory, the drug (or metabolite) is processed by the antigen presenting cells and

subsequently those are expressed in the cell membrane in the background of HLA-A, B or C

type I [(major histocompatibility complex (MHC I)] or HLA-D type II (MHC II) [13]. Via

the T cell receptor, the complex HLA-drug (hapten) is presented to the naïve T cells. Then

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different types of immune responses are initiated based on the cytokine environment as well

as HLA expressed on the antigen presenting cells [14]. Apart from HLA, cytochrome P4502C9

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marker have been reported to be associated with phenytoin-

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induced severe cutaneous adverse reactions [15,16]. It has been found that DRESS syndrome

is more common among slow acetylators of drugs [14]. Table 1 shows some of the high risk
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genetic dispositions to DRESS syndrome with different ethnic population [14-22].

By identifying specific risk allele, prospective HLA screening can prevent some patients
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from having serious idiosyncratic reactions, such as, drug-induced hypersensitivity syndrome
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(DIHS), Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome [17].

The rapidly developing field of HLA pharmacogenomics has, in fact, helped immensely in
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improving drug safety.

3.2.Virus reactivation:
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Inadequate metabolism due to either acquired or pharmacogenetic variation (genetic

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deficiency of detoxifying enzymes like epoxide hydrolase deficiency) results in accumulation

of toxic metabolites (for e.g. arene oxide accumulation in defective metabolism of aromatic

anti-convulsants like carbamazepine, phenytoin and phenobarbitone) which can cause direct

cellular toxicity or immune response [18]. The subsequent activation of immunologic

reactions and reactivation of viruses, most notably, human herpes virus (HHV)-6, HHV-7,

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cytomegalovirus (CMV) and Epstein-Barr virus (EBV) [19–23]. Similarity has been found

between the pattern of the herpes virus re-activation and graft-versus-host disease [24,25].

The sequence of viral reactivation starts with EBV or HHV-6. It goes on to HHV-7 and

finally to CMV [26].As the identification of HHV-6 in blood and disease relapses (e.g., fever,

hepatitis) are temporally related, the viral reactivation may contribute to the phenotype and

severity of the syndrome [26]. These have led to the idea that the initial event in DRESS

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syndrome is a viral reactivation that causes the T cell population to expand by cross-reaction

with the drug. The activated cytotoxic CD8+ lymphocytes directed against virus-related

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antigens then result in tissue damage upon activation [27,28].

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It has been also hypothesized that the culprit drugs may induce reactivation and antigenic

presentation of quiescent forms of EBV or other HHV in cells, such as, B lymphocytes,
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which could secondarily trigger a multi-organ immune response directed against herpes

viruses. The viral reactivation could result in a severe immune response only in susceptible
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people as a result of immune hypersensitivity [29]. Therefore, either an immune response

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against the drug with viral reactivation is a secondary event related to a cytokine storm [30],

or an early viral reactivation with a strong antiviral immune response is responsible for most
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of the manifestations of DRESS [18,31].

However, since latent viruses can be harboured in humans by cells of the immune system
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(principally T lymphocytes and monocytes/macrophages), the reactivation and release of

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viruses may be considered an early marker of stimulation of these cells, rather than the

initiating event in the pathogenesis of DRESS syndrome [32].

HHV-6 reactivation is thought to be the gold standard diagnostic test for DRESS syndrome in

various Asian countries and Europe [33]. But, it is uncertain whether detection of viral

genome detection in blood reflects the actual status of viral reactivation in the body. It is

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likely that various herpes viruses may reactivate in different times in different organs like

lymph nodes and spleen and which is independent of the sequences in blood [33].

Thus, it can be said that DRESS syndrome is primarily a strong immune reaction, specific to

drug, which can consequently boost viral reactivation, leading to various symptoms and

complications. However, more studies are needed to clarify the respective role of viruses and

immune system in this syndrome.

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3.3.Immunological phenomenon:

Drug-specific immune response in DRESS syndrome has been demonstrated in many cases

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by positive patch test[34] and in vitro lymphocyte proliferation assays [35–37]. Patients with

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DRESS syndrome have decreased serum IgA, IgG, IgM, as well as B lymphocytes. There is

also proliferation of memory T cells which can cross-react with both drugs as well as viruses
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[38,39]. It has been reported that several cytokines increase in DRESS syndrome. For e.g.,

pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) are
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elevated even before the reactivation of HHV-6 [40]. However, it has been also found that
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IL-6 levels becomes undetectable in peripheral blood during viral replication process and

again increases after commencement of infection [40]. The phenotype of the circulating T
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lymphocytes is changed from CD4+ to CD8+ at the time of initial viral reactivation.

Regulatory T cell count also increases in the beginning in skin and peripheral blood, but
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decreases subsequently with progress of the disease [40].

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3.4.Drug response:

For anti-convulsant drugs-related DRESS syndrome, three components are important [41]:

i. Deficiency or abnormality of epoxide hydroxylase enzyme which detoxifies the

metabolites of aromatic amine anti-convulsants. This results in the activation

of IL-5 upon accumulation of toxic metabolites resulting in activation of

eosinophils and downstream inflammatory cascade [42,43],

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 ii. Associated cascade of reactivation of HHV family, and

iii. Genetic predisposition to specific HLA alleles.

The common and uncommon drugs causing DRESS syndrome are enumerated in Table 2 [17,

44-107].

Drug interactions also play an important role in DRESS syndrome. For e.g., concomitant use

of lamotrigine and valproic leads to competition between these two drugs for hepatic

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glucuronidation, which doubles the half-life of lamotrigine and predisposed to cause DRESS

syndromes [41].Though expansion of virus-specific and non-specific T-cells including CD8+

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and CD4+ cells is often observed with DRESS syndrome, the mechanism of viral reactivation

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and clinical manifestations is unknown. It has been hypothesized that in addition to clonal

expansion of drug-specific T-cells, cross-reaction of anti-viral T-cells with drugs may result
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in concomitant expansion of viral-specific T-cells [33].
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4. Histopathological findings in DRESS syndrome:

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There are no such specific histopathological findings in skin biopsy that are characteristic of

DRESS syndrome. The macrophage recruitment is caused by the proliferation of CD4+ T

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cells producing interferon and other cytokines, resulting from continuous exposure to drug.

The persistent cytokine level differentiates macrophages to epithelioid cells, which secrete
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TNF-α and finally these cells get fused to form multinucleated giant cells [17].
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The following findings, such as, non-specific lymphocytic infiltration, typically in the

perivascular superficial dermis, abundance of eosinophils, band-like infiltrate of atypical

lymphocytes, involvement of the papillary dermis, dermal edema, spongiosis, acanthosis,

vacuolization, and epidermotropism may be present which also resembles mycosis fungoides

[108–110]. A study involving 36 patients suffering from DRESS syndrome evaluated 50 skin

biopsies and showed that the most frequent histopathologic pattern was an interface

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dermatitis often involving the pilar units, followed by eczematous, erythema multiforme-like

pustulosis and acute generalized exanthematous pustulosis [111]. Of note, more than one

histologic pattern was frequently observed in a single biopsy. Atypical lymphocytes,

sometimes resembling Sézary cells, were present in approximately one-third of cases.

Lymphocytes phenotyping showed a predominance of CD8+ lymphocytes, with numerous

cytotoxic cells expressing granzyme B [111].

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5. Clinical features:

The time of onset is usually delayed, and it ranges from 2-6 weeks after initiation of

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treatment [7]. Though usually delayed in onset, UM et al. reported that clinical manifestation

might present from 3-105 days [112]. The major clinical manifestations of this syndrome are
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fever, skin rash, eosinophilia, lymphadenopathy and involvement of visceral organs like liver,
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kidney, heart, etc. [13]. Besides these, there are case reports of some unusual presentation

like dysphagia, oral ulceration [113–115], hematological abnormalities other than

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eosinophilia, myalgia and arthritis [116]. These clinical features usually vary among the

patients. The clinical features along with the frequency of presentations are presented in
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Table 3 [116-117].

The most common clinical feature of this syndrome is fever, which is usually high grade
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ranging from 38-400C [122]. An unusual fever pattern known as ‘typhus inversus’ in which
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temperature is highest in the morning time and lowest in the evening (reverse to normal

pattern) has been reported by Ben-Ari et al. [123]. The second most common feature is rash,

which presents as macular erythema at the beginning, followed by papular lesions with or

without pruritus involving upper trunk and face which later even progresses to lower

extremities [124]. The cutaneous manifestations typically consist of an urticarial,

maculopapular eruption and, in some instances, vesicles, bullae, pustules, purpura, target

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lesions, facial edema, cheilitis, and erythroderma [125,126]. Lymphadenopathy is the third

most common presentation which is seen in 70-75% of patients [116–121], either generalized

or limited to lymph nodes, painful and gradually resolves after withdrawal of the offending

drug [117]. Hematological abnormalities, such as, leukocytosis, eosinophilia, and atypical

lymphocytosis are typical features. Kato et al. have reported agranulocytosis as an atypical

hematological feature of DRESS syndrome [127].

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The most common visceral organ involved in DRESS syndrome is liver, which is usually

present in 50-60% of patients. Features of liver involvement range from mild elevation of

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liver enzymes and hepatitis (moderate) to severe fulminant hepatitis [124]. Acute hepatitis is

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a common manifestation of DRESS syndrome. A case of acute hepatitis in DRESS syndrome

induced by sulfasalazine has been reported by Oliveira et al.[128]. Severe acute hepatitis
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caused by piroxicam has also been reported in DRESS syndrome [129]. Acute liver failure

has been reported in patients taking valproate and Leflunomide by van et al. [130] and Vaish
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et al. [131] respectively in two case reports. The second most common visceral organ
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involved in this syndrome is kidney where the clinical features range from hematuria in the

mild form to nephritis in moderate form and acute renal failure in the severe form [124].
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Many authors have cases of nephritis in patients suffering from DRESS syndrome [116–121].

Furosemide-induced acute kidney injury [132], sulfasalazine [133] and vancomycin [134]-
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induced delayed acute interstitial nephritis have also been reported. Lungs are involved in
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6.7-10% patients, which are the third common visceral organ involved in DRESS syndrome.

A mild cough in initial stage can progress to pneumonitis and acute respiratory distress

syndrome in the later stage [124]. Two cases of pulmonary involvement in DRESS syndrome

has been reported due to anti-retroviral therapy[135] and homeopathic medicine [136].

Chylous ascites is also reported in DRESS syndrome [137]. Kumariet al. have reported

muscle involvement in this syndrome which may range from mild elevation in creatinine

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kinase level to myositis in moderate form and rhabdomyolysis in severe cases [124]. DRESS

syndrome presenting as leukoencephalopathy have been reported in a child taking phenytoin

and phenobarbitone [138]. Cardiac involvement in this syndrome is reported by Thongsriet

al.[139],which can present as pericarditis in the mild form, carditis in moderate and

congestive heart failure in severe form [124]. There are also reports of myocarditis [140] and

fulminant myocarditis [141] in patients with DRESS syndrome. This syndrome can also

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present as pancreatitis involving elevation of the pancreatic enzyme [142]. A case of

encephalopathy with stroke has also been reported by Vidula et al. [143]. Cicatrizing

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conjunctivitis involving all palpebral conjunctival surfaces with evidence of sub-epithelial

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fibrosis in a patient with DRESS syndrome receiving lamotrigine and levetiracetam has been

reported by Bohm et al. [144]. Table 4 shows some atypical presentations of DRESS
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syndrome. [81-85, 113, 123, 133, 144].
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6. Diagnostic criteria:
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There are different criteria for the diagnosis of DRESS syndrome, such as,

i. Bocquet’s criteria [145],

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ii. The European Registry of Severe Cutaneous Adverse Reactions to Drugs and

Collection of Biological Samples (RegiSCAR) criteria [93], and

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iii. The Japanese group of Severe Cutaneous Adverse Reactions to Drugs (SCAR-J)
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criteria [94].

RegiSCAR criteria is simple and widely acceptable [54]. It distributes scores based on

clinical features finally dividing them into definite (score, >5), probable (score, 4-5), possible

(score, 2-3) and no (score, <2 ) DRESS syndrome [146,147]. Kim et al.[148] have compared

these three diagnostic criteria as shown in Table 5. Table 6 enumerates the scoring system for

classifying DRESS syndrome [149].

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 7. Differential diagnosis:

The most common differential diagnoses of DRESS syndrome [124,150] are enumerated in

Table 7. There are also some overlaps between DRESS and viral exanthema especially EBV

infectious mononucleosis. Thorough survey of viral panel is recommended across different

guidelines [8]. Differential diagnosis also includes viral exanthema, graft versus host disease,

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adult onset still’s disease [151].

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8. Management:

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The proper management of DRESS syndrome is important because of its potential risks
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[152]. There are some common overlapping clinical features between this syndrome and

other severe cutaneous adverse drug reactions, such as, Stevens-Johnson syndrome, toxic
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epidermal necrolysis and hypereosinophillic syndrome etc. Management of DRESS

syndrome involves appropriate intensive care and infection control. Treatment is mainly
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supportive and symptomatic [7]. Initial suspicion and identification of the culprit drug(s) is of

paramount importance. The management starts with immediate withdrawal of the suspected
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drug(s). Laboratory tests like patch test or lymphocyte transformation test may help in
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diagnosis and can be used judiciously [153,154]. Treatment in patients with exfoliative

dermatitis involves appropriate fluid and electrolyte management along with nutritional
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support. Additional measures include involvement of nursing care in a warm and humid

atmosphere, appropriate skin care by taking with warm baths or using wet dressings and use

of emollients [153]. The general treatment options for DRESS syndrome are as follows:

i. Anti-histamines,

ii. Oral corticosteroids,

iii. Pulsed corticosteroid with methylprednisolone,

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 iv. Intravenous immunoglobulin (IVIG),

v. Anti-viral drugs (ganciclovir),

vi. Combination of one or more drugs from above class, and

vii. Plasmapheresis.

For symptomatic relief of pruritus and skin inflammation, H1 anti-histamines and high

potency topical corticosteroids can be used [155]. Prompt withdrawal of the offending

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drug(s) is the main stay of therapy in case of liver involvement. The expert opinion of French

Society of Dermatology, 2010 recommended systemic corticosteroid use in case of organ

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involvement, such as, liver (transaminases >5times upper limit of normal), kidney, lungs and

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heart. Prednisone(or equivalents) at a dose equivalent to 1 mg/kg/day can be used with any

sign of severity, such as, involvement of [20]. Severe hepatocellular damage may evolve to
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acute liver failure, and the only effective therapy may be liver transplantation. Patients with

severe hepatitis, particularly those with jaundice, should be promptly referred to a liver
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transplant specialist [156]. For patients with lung or kidney involvement, systemic
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corticosteroids can be used until the patient improves clinically and laboratory parameters

become normal. Pulsed Methylprednisolone therapy is sometimes required. The dose of

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steroid therapy and duration of corticosteroid therapy are not well known [157].

Cyclosporine may be considered as a second-line therapy for patients with severe organ
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involvement who do not respond to systemic corticosteroids and for patients in whom
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corticosteroids are contraindicated [158–160]. IVIG have also been reported as beneficial in

a few patients with DRESS syndrome and detrimental in others [20,160–162]. Anti-

viral agents may be warranted for these patients in whom virus reactivation is demonstrated

and suspected of contributing to severe complications (e.g., encephalitis, hemophagocytosis

or severe erosive colitis) [163]. Periodical monitoring (both clinical and laboratory

parameters) is necessary for progression of the skin eruption and/or development of clinical

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or laboratory symptoms related to organ involvement. The important laboratory parameters

include complete blood count (CBC), liver function tests (LFT), renal function tests (RFTs)

etc. [157].

N-acetyl cysteine (NAC) can be used in DRESS syndrome which act by detoxifying drug

[164]. Successful therapeutic plasmapheresis for the management of DRESS syndrome has

also been reported in some literature [165,166]. Finally, the treatment of DRESS syndrome

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should be started without delay. This may happen while waiting for the result of viral

markers. [167]. Further studies with appropriate designs (e.g. randomized controlled trials)

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are needed for establishing a standard of care in DRESS syndrome.

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According to the expert opinion of French society of dermatology, 2010, DRESS/DIHS can

be managed based on the presence or absence of signs of severity. In case of absence of

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severity signs, the patient can be managed symptomatically with topical steroids emollients,

and H1 anti-histamines. Elevated liver transaminases more than five times of upper limit of
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normal, involvement of kidney, heart, lungs (pneumonia), and hemophagocytosis etc. warrant
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management with corticosteroids equivalent to 1 mg/kg per day of prednisone, and

multidisciplinary involvement. Fatal life-threatening signs which include hemophagocytosis

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with bone marrow failure, encephalitis, severe hepatitis, renal failure, and respiratory failure

require treatment with steroids generally administered with intravenous IVIG at a dose of 2
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g/kg over 5 days. The IVIG should not be administered in the absence of steroids. In the
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scenario of confirmed major viral reactivation along with presence of severity signs, the

patients warrant combination of steroids and anti-viral medications (e.g. ganciclovir) with or

without IVIG.

9. Prognosis and prevention:

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After discontinuation of causative drug, most of the patients take weeks to months to recover

completely. The prevalence of sequelae is unknown. Patients are required to be monitored for

manifestations of autoimmune diseases [168,169], which might lead to chronic organ failure

[170]. Long-term sequelae were may lead to renal failure, chronic anemia, autoimmune

diseases (autoimmune thyroid disease and autoimmune hemolytic anemia) [171]. Laboratory

monitoring, including autoantibodies and thyroid stimulating hormone, also may be

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warranted based upon clinical findings. Patients who recover from DRESS syndrome may

have an increased risk of reaction to structurally unrelated drugs [27]. The risk appears to be

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higher in the first few months. Patients should be educated about the need for a strict

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avoidance of the offending as well as cross-reacting drugs [172]. Although the mortality is

low [173], early diagnosis can decrease the mortality due to this syndrome.
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10. Conclusion:

The DRESS syndrome, a serious, life-threatening hypersensitivity reaction has been linked to
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various genetic factors, viruses, immunological phenomenon and drugs. The clinical features

vary widely among different patients. Among the different diagnostic criteria (Bocquet’s
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criteria, RegiSCAR criteria and Japanese group’s criteria), RegiSCAR is most commonly

used one. The management of this condition includes treatment with anti-histamines,
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emollients, corticosteroids and plasmapheresis along with other alternatives drugs depending
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on the severity of the manifestations. As early diagnosis and treatment improve outcomes

considerably, healthcare professionals should be more vigilant for early diagnosis of this

syndrome.

Transparency

Declaration of funding

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This paper was not funded.

Declaration of financial/other interests

The authors have no relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript. This includes employment, consultancies, honoraria, stock

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ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to

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disclose.

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141 Bourgeois GP, Cafardi JA, Groysman V, Pamboukian SV, Kirklin JK, Andea AA, et
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al. Fulminant myocarditis as a late sequelae of DRESS-2 cases. J Am Acad Dermatol

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144 Bohm KJ, Ciralsky JB, Harp JL, Bajaj S, Sippel KC. Cicatrizing Conjunctivitis in a

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146 Grover S. Severe cutaneous adverse reactions. Indian J Dermatol Venereol Leprol

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147 Peyrière H, Dereure O, Breton H, Demoly P, Cociglio M, Blayac J-P, et al.

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149 Chan J, Chan H, Yeung C. Drug reaction with eosinophilia and systemic

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150 Cardoso CS, Vieira AM, Oliveira AP. DRESS syndrome: a case report and literature
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151 Bachot N, Roujeau J-C. Differential diagnosis of severe cutaneous drug eruptions.
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156 Davern TJ. Drug-induced liver disease. Clin Liver Dis 2012; 16:231–245.

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159 Kirchhof MG, Wong A, Dutz JP. Cyclosporine Treatment of Drug-Induced

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170 Matta JMR, Flores SM, Cherit JD. Drug reaction with eosinophilia and systemic

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ce

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Ac

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34
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2013; 169:1071–1080.

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an
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ed
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35
Table 1: Some genetic linkage to DRESS syndrome with different ethnic population.

Drugs Populations Genetic linkages

Han Chinese-Taiwan [14,15] rs2894342 (motilin gene) [15]
Carbamazepine Caucasian European [16] Haplotypes TNF-308- DR3-DQ2 [16]
Southeast Asian [16] Unknown [16]
Han Chinese-Taiwan [17] HLA-B*5801 [17]
Allopurinol Caucasian European [17] HLA-B* 5801 [17]

t
Han Chinese-Singapore [18] HLA-B17/BW58 [18]

ip
Caucasians [19] HLA-B*5701 [19]
Abacavir
Hispanic or Africans [20] No association with HLA-B*5701 [20]

cr
Australian [21] HLA-DRB1*0101 [21]
Nevirapine
Thai [22] HLA-B*3505 [22]
Phenytoin Thai [15,16] Cytochrome P4502C9 [15,16]

us
an
M
ed
pt
ce
Ac

36
Table 2: Common and uncommon drugs causing of DRESS Syndrome
Drug classes
Aromatic anti-epileptics
Other anti-epileptics
Antibiotics
Antitubercular drugs
Xanthine oxidase inhibitors
Non-steroidal anti-
inflammatory drugs
Immunomodulators/
immunosuppressants
ed
Anti-rheumatic drugs
Anti-retrovirals
pt
Anti-hepatitis drugs
ce
Psychopharmaceuticals
Anti-cancer drugs
Ac
Miscellaneous agents
Common drugs Uncommon drugs
Carbamazepine,
phenytoin, Oxcarbazepine [44]
phenobarbitone
Levetiracetam [45], valproic acid[46],
Lamotrigine
rufinamide[47], zonisamide[17]
Amikacin [48], amoxicillin [49,50],
t
azithromycin [51], cefadroxil [17],
ip
cefotaxime [52], ceftazidime [53],
Trimethoprim- ceftriaxone [54], ciprofloxacin [55,56],
cr
sulfamethoxazole, dapsone [57,58], linezolid [59], levofloxacin
minocycline, [60], meropenem [61], teicoplanin [62],
dapsone nitrofurantoin [63], minocycline [64],
us
vancomycin [65,66], vancomycin and
teicoplanin [67], penicillin [68], piperacillin
[69], piperacillin-tazobactam [62,63]
Isoniazid [71], ethambutol and rifampicin
an
[72], prothionamide and para-aminosalicylic
acid [73], streptomycin[17]
Allopurinol Febuxostat [74]
M
Aspirin [75], celecoxib[17], ibuprofen [76],
paracetamol [77], phenylbutazone [78]
Lenalidomide [79], everolimus [80]
Sulfasalazine, Leflunomide [81], hydroxychloroquine [82],
gold salts efalizumab[17]
Nevirapine [83,84], cidofovir [85], tenofovir
Abacavir
[86], raltegravir[87]
Boceprevir [88], peginterferon α-2a and
ribavirin[89], telaprevir [90]
Fluoxetine [91], olanzapine [92],
amitriptyline[17], clomipramine[17]
Vemurafenib [93,94], vismodegib [95],
imatinib [17]
Bosentan [96], captopril [97], chloral
hydrate [98], deferasirox [99], omeprazole
[100], esomeprazole [101], enoxaparin
[102], fenofibrate [103], metformin [104],
hydrochorothiazide [105], potassium-para
aminobenzoicacid[106], diindolylmethane
[107], atorvastatin[17], clopidrogrel[17],
codeine [17], mexiletine[17], quinine [17],
thiamine[17], spironolactone[17]
37
Table 3: Clinical features of DRESS syndrome with frequency of presentation

Percentages
Clinical features
References [117–121] Reference [116]
Fever 90-100 86.59
Rash 87-90 84.6
Lymphadenopathy 70-75 70
Eosinophilia 25 69.2
Hematological abnormalities 23-50 -

t
Elevated liver transaminases 51 90.4

ip
Liver involvement or hepatitis 50-60 -
Facial swelling with periorbital
25 26.9

cr
involvement
Myalgia and arthritis 20 -
Nephritis 11 8.7

us
Multi-organ involvement
[myocarditis/myositis, pericarditis, 11 18.3
interstitial nephritis)
Pharyngitis 10 -
an
Pulmonary manifestations 9 6.7
Death or liver transplantation 15 -
M
ed
pt
ce
Ac

38
Table 4: Some atypical presentations in DRESS syndrome

Atypical presentations Examples of drugs involved

Agranulocytosis [81] Sulfasalazine
Chylous ascites [82] Amoxicillin-clavulanic acid
Cicatrizing conjunctivitis [144] Lamotrigine, levetiracetam
Dysphagia [113] Amoxicillin
Delayed acute interstitial nephritis [133] Sulfasalazine
Leukoencephalopathy [83] Phenobarbitone, phenytoin
Oral ulceration [84] Celecoxib, ethambutol
Pneumothorax and pneumomediastinum [85] Phenobarbitone

t
Typhus inversus type fever [123] Paracetamol, phenytoin, metamizole

ip
cr
us
an
M
ed
pt
ce
Ac

39
 Table 5: Comparison of three diagnostic criteria in DRESS syndrome
Bocquet criteria
All the following 3 criteria
are essential
Criteria
1. Cutaneous drug eruption
2. Internal organ
involvement:
Lymphadenopathies (>2
cm in diameter), hepatitis
(transaminases value >2
times upper limit of
normal), interstitial
nephritis, and interstitial
pneumonia or carditis
3. Hematologic
abnormalities:Eosinophil
count >1.5×103/µL or
presence of atypical
ed
lymphocytes
pt
HHV-6: Human herpes virus-6
ce
Ac
RegiSCAR criteria SCAR-J criteria
• Typical DRESS: all 7
criteria are essential
>3 criteria are required* • Atypical DRESS: all
criteria are essential except
lymphadenopathy and HHV
6 reactivation
t
ip
1. Hospitalization 1. Maculopapular rash
2. Reaction suspected to be developing >3 weeks after
cr
drug-related starting a limited number of
3. Acute rash* drugs
4. Fever above 38°C* 2. Persistent clinical
us
5. Enlarged lymph nodes symptoms 2 weeks after
involving at least two discontinuation of causative
sites* drug
6. Involvement of at least 1 3. Fever above 38°C
an
internal organ* 4. Liver transaminases level
7. Blood count (ALT) >100 U/L or other
abnormalities: organ involvement
• Lymphocytes above or 5. Leukocyte abnormalities [at
M
below normal laboratory least 1): leucocytosis
limit* (>11×109/L), atypical
• Eosinophil count lymphocytosis (>5%),
eosinophilia (1.5×109/L)
above laboratory limit*
• Platelets below 6. Lymphadenopathy
laboratory limit* 7. HHV-6 reactivation
40
 Table 6: Scoring system[141] for classifying DRESS syndrome

Scores
Clinical manifestations
-1 0 1 2 Min. Max.
General
Fever ≥38.5o C No/unknown Yes - - -1 0
Enlarged lymph nodes - No/unknown Yes - 0 1
Eosinophilia

t
No 0.7-1.49 x ≥1.5 x
Eosinophil count -

ip
eosinophilia 109/L 109/L 0 2
Eosinophil (%), if leucocyte
- - 10-19.9% ≥20%
count <4.0x109/L

cr
Atypical lymphocytes - No/unknown Yes - 0 1
Skin involvement
Extent (% of body surface

us
- No/unknown >50% -
area)
-2 2
Skin rash suggesting DRESS No Unknown Yes -
Yes/Unknow
Skin biopsy suggesting DRESS No
an - -
n
Organ involvement (score 1: 1 organ involvement, score 2: ≥2 organs involvement)
Liver - No/unknown Yes -
M
Kidney - No/unknown Yes -
Lung - No/unknown Yes - 0 2
Muscle/heart - No/unknown Yes -
Pancreas - No/unknown Yes -
ed

Other organ - No/unknown Yes -

No/unknow
Resolution ≥15 days Yes - - -1 0
n
pt

Evaluation of other potential causes

(If none is positive and ≥3 of
the following are negative)
ce

• Antinuclear antibody 0 1
• Blood culture - - Yes -
• Serology for hepatitis A/
Ac

hepatitis B/hepatitis C
• Chlamydia/Mycoplasma
Total Score -4 9

Max: maximum, min: minimum

Interpretation based on final score:

>5: definite, 4-5: probable, 2-3: possible, <2: no case

41
 Table 7: Differential diagnoses of DRESS syndrome

Diseases Stevens-
Serum
Johnson Hypereosino
Kawasaki Pseudolym sickness-
syndrome/Tox philic
disease phoma like
Usual clinical ic epidermal syndrome
reaction
manifestations necrolysis
Approximate
1-3 weeks 2 weeks ≥5 years 6 months 7-14 days
onset

t
Conjunctival

ip
congestion,
fissured lips,
Urticaria,

cr
strawberry
angioedema,
Blisters, tongue, palmar
morbilliform Single or Urticarial
Mucocutaneo mucous erythema
General eruption, multiple exanthemat

us
us features membrane edema of
infiltrated nodules ous rash
involvement hands,
papules or
periungual
nodules
desquamation,
an
polymorphous
exanthema
Fever Present Present/absent Present Absent Present
M
Arthralgia Present/absent Present Present Absent Present
Hematol Eosinophilia Absent Present Absent
ogical Presence of
abnorma atypical Absent Absent Absent Present Absent
ed

lities lymphocytes
Lymphadenop
Absent Present Present/absent Present Present
athy
Systemic Present/abse Present/abs
pt

Hepatitis Present Present Present/absent

involvem nt ent
ent Other internal
Present/abse
organ Present Present Present Absent
ce

nt
involvement
Ac

42