Drug reaction with eosinophilia and systemic symptoms: An emergency medicine focused review

a b s t r a c t

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction associ- ated with potentially severe morbidity and mortality.

Objective: This narrative review evaluates the pathogenesis, diagnosis, and management of DRESS for emergency clinicians.

Discussion: DRESS is a severe hypersensitivity reaction which can involve multiple organ systems, including the skin, lymphatic system, lungs, kidneys, and heart. Treatment is primarily supportive care combined with removal of the offending agent and initiation of corticosteroids. Additional options include cyclophosphamide, cyclospor- ine, intravenous immunoglobulin, and N-acetylcysteine.

Conclusion: It is important for the emergency clinician to be aware of the diagnosis and management of DRESS in order to best optimize care for these patients.

(C) 2022

  1. Introduction

A variety of Adverse drug reactions were first reported in the 1930s [1,2]. Then, in the 1950s, Chaiken et al. reported a case of exfoliative dermatitis, hepatitis, and fever associated with phenytoin [3]. Following this report, several other cases were reported describing similar find- ings in patients taking antiepileptic medications [1,4-6]. The term “drug rash with eosinophilia and systemic symptoms” was first used in 1996 by Bocquet et al. [7] However, as dermatosis is not mandatory for the diagnosis of DRESS, the “R” was later modified to “reaction” [2,8]. Adverse drug reactions with skin involvement can be broadly sepa- rated into Severe reactions (e.g., DRESS, toxic epidermal necrolysis, Stevens-Johnson Syndrome) and more limited reactions (e.g., serum sickness-like reactions, drug-induced dermatoses). DRESS is a severe reaction that is estimated to occur in up to 2 cases per 100,000 patients per year [9,10], with a population-level risk between 1 in 1000 and 1 in 10,000 drug exposures [11]. However, DRESS accounts for up to 20% of patients admitted with a cutaneous drug adverse event, and has a mortality rate of nearly 10% [2,12-14]. While DRESS is more common in adults, it has also been described in pediatric patients [15]. Numerous medications have been associated with DRESS, and a specific drug is identified as the causative agent in approximately 80% of cases [8]. However, in 10-20% of cases, an association with a medication is un- clear [8]. Approximately three-quarters of cases with an identified

* Corresponding author.

E-mail address: [email protected] (M. Gottlieb).

cause are associated with allopurinol, Aromatic anticonvulsants (e.g., carbamazepine, lamotrigine, phenytoin), proton pump inhibitors, antibiotics containing sulfonamides, minocycline, or vancomycin (Table 1) [2,8,16]. In the United States, the increasing use of vancomycin has led to it being the most common causal agent [17]. Interestingly, the risk of DRESS may be dose dependent for several drugs, including allopurinol, especially in those with Renal impairment [18].

Unfortunately, DRESS can present with myriad symptoms and can be challenging to diagnose. In light of these challenges and the signifi- cant mortality rate, it is essential that emergency clinicians are aware of this important condition.

  1. Methods

This narrative review will characterize DRESS and provide updates in the evaluation and management for the emergency clinician. The au- thors searched PubMed for articles using the keywords “DRESS” OR “Drug Reaction with Eosinophilia and Systemic Symptoms”. The search was conducted from the database’s inception through February 1, 2022 and yielded 2349 articles. Authors evaluated case reports and series, retrospective and prospective studies, randomized controlled trials, systematic reviews and meta-analyses, and other narrative reviews. Authors also reviewed guidelines and supporting citations of included articles. The literature search was restricted to studies published in English, with a focus on the emergency medicine and critical care liter- ature. Authors decided which studies to include for the review by

0735-6757/(C) 2022

Medications associated with DRESS [2,8,16]. Differential Diagnosis for DRESS.



Condition Presentation


antituberculosis medications (e.g., ethambutol, isoniazid, pyrazinamide, rifampicin)

Aromatic antiepileptic medications (e.g., carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin) Mexiletine

Minocycline Nevirapine Vancomycin

Acute Generalized Exanthematous Pustulosis

AGEP is a pustular drug eruption in response to specific medications. AGEP will typically have a faster onset (2-3 days), shorter resolution (< 1 week), and more mucosal involvement when compared with DRESS. Laboratory studies would demonstrate a neutrophilic predominance, rather than the eosinophilic predominance seen with


Lower-risk medications

Beta-lactams (e.g., amoxicillin, ampicillin, piperacillin) Fluoxetine


Nonsteroidal anti-inflammatory drugs (e.g., celecoxib, diclofenac, ibuprofen)

Omeprazole Raltegravir Sorafenib Vemurafenib

Adult-Onset Still’s Disease Adult-onset Still’s Disease is a systemic

inflammatory disorder of unknown etiology, which commonly affects young adults. It differs from DRESS because it mostly affects young adults while DRESS can affect any age. Additionally, the rash is usually nonpruritic, macular, and salmon colored affecting predominately the trunk and extremities while the rash associated with DRESS is more generalized in location.

Atopic Dermatitis Atopic dermatitis, a form of eczema, is a pruritic

consensus. When available, systematic reviews and meta-analyses were preferentially selected. These were followed sequentially by randomized controlled trials, prospective studies, retrospective studies, case reports, and other narrative reviews when alternate data were not available. A total of 70 resources were selected for inclusion in this narrative review by author consensus.

  1. Discussion
    1. Pathophysiology

While DRESS is believed to be a hypersensitivity reaction to a drug or its metabolites, the exact pathogenesis has not been fully elucidated. It is likely related to one or more of the following factors: an abnormality or deficiency in the epoxide hydroxylase enzyme which detoxifies certain

Cutaneous Pseudolymphoma (CPSL)

eruption and the most common chronic inflammatory skin disease. It differs from DRESS by the typical location of the rash. Atopic dermatitis usually appears on the face in infancy and then in antecubital fossa in children and adults while the rash associated with DRESS is more generalized and can occur at any age. Fever and additional organ involvement would not be expected with atopic dermatitis.

Cutaneous pseudolymphoma refers to a heterogenous group of benign reactive T or B cell lymphoproliferative processes of diverse causes that simulate cutaneous lymphomas clinically and/or histologically. This rash differs from DRESS by its onset being 6 months or later which is later onset than DRESS. CPSL’s Inflammatory infiltrate is also predominantly lymphocytic with or without other inflammatory cells while DRESS has a predominance of eosinophils.

medications (e.g., aromatic amine anticonvulsants), a predisposition

with several human leukocyte antigen (HLA) alleles, human Herpesviridae reactivation, and T-cell mediated hypersensitivity [19]. Deficient drug metabolism and reactive metabolites due to abnormal epoxide hydroxylase enzymes may explain the predisposition of certain

Erythroderma Erythroderma is a clinical finding characterized by

diffuse erythema and scaling of greater than 90% of the body surface area and is a reaction to a variety of causes including psoriasis, eczema, or certain drugs. When compared to DRESS, it is less likely to have a fever and eosinophils are not as prevalent.

populations. Mutations in these enzymes can result in toxic metabolite accumulation, resulting in a hypersensitivity reaction [2,20]. These mutations may be autosomal dominant. Specific HLA haplotypes (including HLA-B*5701, HLA-A*3101, and HLA-B*5801) are another predisposing factor [2,21,22].

Human Herpesviridae reactivation with antiviral immune response

Hypereosinophilic Syndrome (HES)

Hypereosinophilic syndrome constitutes a rare and heterogenous group of disorders, defined as persistent blood eosinophilia (>11.5 x 109/L for more than 6 consecutive months) associated with eosinophil-induced organ damage. This disease differs from DRESS by the timeline and absence of linkage to a precipitating medication.

may also contribute [2,7,8,23,24]. Viruses in this family include HHV-6, HHV-7, Epstein-Barr virus, and cytomegalovirus [25-29]. Among these, HHV-6 is the most common virus associated with DRESS, with reactiva- tion of HHV-6 accounting for 16-60% of all cases [8,25-30]. Typically, reactivation occurs within weeks, peaking two to three weeks after initial presentation [8,25-30]. Despite this association, the exact mecha- nism of viral reactivation is not clear. One proposed mechanism is that certain medications (e.g., Valproic acid) can directly increase viral- specific replication, leading to reactivation [31].

Finally, T cell-mediated hypersensitivity likely plays a role, as the

acute phase of the disease is associated with CD4 and CD8 T cell activa- tion and expansion [24,32-35]. Certain subsets of CD4 and CD8 cells may have antigen receptors that increase the risk of developing DRESS [24,32-35]. The expansion of these cells may also help to explain the role that viral reactivation plays in the acute setting.

    1. Differential diagnosis

There are a variety of conditions which can appear similar to DRESS. Table 2 provides a summary of these conditions and both similarities and differences with DRESS.

Kawasaki disease KD is an acute, self-limited medium vessel vasculitis

that has a predilection for coronary arteries. This disease differs from DRESS syndrome by the presentation of the rash which will typically have a patchy generalized macular erythematous rash over the trunk and extremities that appears within 5 days of fever and is usually nonpruritic. More specifically, patients with KD typically have peeling of the skin in the periungual area that starts 2-3 weeks after onset of fever which is also not seen in DRESS.

necrotizing fasciitis Necrotizing fasciitis is a rare but potentially fatal

infection involving the subcutaneous tissue and fascia. This differs from DRESS because of the degree of pain and focality, as it is a deep tissue injury associated with bacterial infection. It may also be associated with crepitus and bullae.

Psoriasis Psoriasis is a chronic proliferative and inflammatory condition of the skin. It causes a pruritic rash that consists of papules and plaques with silvery scales. It differs from DRESS because this rash has a predilection for the knees and elbows. Psoriasis is also associated with nail pitting and positive Auspitz sign (pinpoint bleeding spots from exposure of dermal papillae when scales are scraped off) not seen with DRESS.

Table 2 (continued)

Condition Presentation

Serum Sickness Serum sickness is an immune-complex-mediated

hypersensitivity reaction that classically presents with fever, rash, and polyarthritis. It differs from DRESS due to the joint involvement and less pronounced fever.

SJS/TEN SJS/TEN are rare diseases characterized by widespread epidermal necrosis and sloughing of skin. These rashes differ from DRESS by their associated symptoms. Additionally, the Liver enzymes are more commonly elevated in DRESS compared to SJS/TEN. Additionally, mucosal involvement (e.g., oral cavity, eyes, genitalia) is more pronounced in SJS/TEN compared to DRESS.

Lymphadenopathy can be present in the cervical, axillary, or inguinal re- gions [24]. Lung involvement is seen in 32% of patients [8,37], and can include pneumonitis, Pleural effusions, pneumonia, and even acute re- spiratory distress syndrome (ARDS) [44]. Patients may present with symptoms such as dyspnea, cough, chest pain, or other manifestations of pulmonary disease. cardiac involvement is seen in only 4 to 15% of patients [37,41], and can include symptoms such as chest pain, palpita- tions, tachycardia, and hypotension in some cases [45].

    1. Diagnosis

When considering DRESS syndrome, clinicians should obtain a com- plete blood count with differential, basic metabolic panel, liver function

Staphylococcal Scalded Skin Syndrome

SSSS is a disease characterized by erosion of the skin caused by exotoxin producing strains of staphylococcus species. It differs from DRESS in its timeline and predilection for pediatric patients. It is also unique and different from DRESS because it involves sloughing of upper layers of epidermis that heals completely.

testing, urinalysis, and a chest radiograph. The most common laboratory

finding is eosinophilia (defined as an eosinophil count >=700 uL-1), which can be seen in 30 to 95% of patients [8,37,42,43]. One study reported that 81% of patients had an eosinophil count >=1500 uL-1 [8]. Leukocytosis was seen in 52 to 95% of patients who were diagnosed with DRESS [8,37]. Similarly, thrombocytosis, an acute phase reactant,

AGEP, Acute Generalized Exanthematous Pustulosis; CPSL, Cutaneous Pseudolymphoma; HES, Hypereosinophilic syndrome; KD, Kawasaki Disease; SJS, Stevens-Johnson Syndrome; TEN, Toxic Epidermal Necrolysis; SSSS, Staphylococcal Scalded Skin Syndrome.

    1. Clinical features

DRESS can be challenging to detect due to the variation in clinical presentations. There is often a latency period between the initiation of the offending medication and the beginning of symptoms. Data suggest the latency period can range from 1 to 12 weeks [24,36-39]. The most common feature of DRESS is dermatologic findings, with a rash occurring in nearly 99% of patients (Fig. 1) [40]. The most common man- ifestation is an exanthematous, macular-papular rash starting at the trunk, which can be seen in 48 to 100% of patients [11,24,37,41]. The rash is often distributed symmetrically across the body [24,40]. The rash can be large, with one study reporting that 79% of patients had a rash exceeding over half of their body surface, and the majority of rashes persist for two weeks or longer [8]. Facial edema is also common, with one study reporting that it was present in over half of all cases (65% of major cases and 32% of minor cases) [42]. Skin involve- ment can also affect mucosal surfaces, leading to dysphagia in some patients [8].

While the most common symptom is a rash, fever is also frequently present and has been reported in 72 to 100% of patients [11,37,41-43]. Lymphadenopathy is seen in 50 to 88% of patients [40-43].

can be seen in 25% of patients [37].

The liver is the most commonly involved organ besides the skin, affected in 51 to 100% of cases [8,11,30,37,42,43]. Elevated liver enzymes are present in over half of cases [30]. Renal dysfunction (including elevation of creatinine or proteinuria) is also common, occur- ring in 11 to 53% of patients presenting with DRESS syndrome [37,40,43,46]. Allopurinol specifically has been associated with an increased risk of renal dysfunction among patients with DRESS [8].

A chest radiograph will be abnormal in approximately half of cases, with the most common findings including interstitial infiltrates (50%), ARDS (31%), and pleural effusions (22.7%) [44]. While not generally per- formed by emergency clinicians, dermatologists may decide to obtain a skin biopsy.

There are several diagnostic tools which have been described that typically rely on a combination of history, physical examination, and di- agnostic testing. Bocquet et al. proposed a simple tool involving three main criteria (Table 3) [7]. The RegiSCAR group created a more complex scoring tool involving eight components that grades outcomes from definite DRESS to not DRESS (Table 4) [8]. Shiohara created another de- cision tool which includes both a typical and atypical option [47] (Table 5). One study of 48 patients diagnosed with DRESS comparing all three criteria found that 93.3% met RegiSCAR probable (or more) criteria, 60.4% met RegiSCAR definite criteria, 77.1% of patients satisfied Bocquet criteria, and 18.8% satisfied Shiohara atypical DIHS criteria [48]. Based upon these data, we recommend RegiSCAR as the preferred tool for diagnosing DRESS.

Image of Fig. 1

Fig. 1. A, Morbilliform rash on the trunk; B. Erythematous papular rash on the feet. Images courtesy of Mohammed et al. [70].

Table 3

Bocquet et al. Criteria for DRESS [7].

DRESS is confirmed by the presence of all three findings:

      1. Cutaneous drug eruption
      2. Lymphadenopathy >2 cm in diameter, liver enzymes >2 times the Upper limit of normal, interstitial nephritis, interstitial pneumonitis, or carditis
      3. Eosinophil count greater than >=1500 uL-1 or atypical lymphocytes
    1. Management

Current recommendations involve a combination of administering supportive care, discontinuing the culprit drug, and reducing the inflammatory cascade [49]. Early management should involve antipy- retics and intravenous hydration as needed [49]. Empiric antibiotics should be avoided as they have the potential to exacerbate the clinical condition due to cross-reactivity [23,50]. If the causative medication is identified, it should be stopped as soon as possible [49,51]. An 11-year retrospective study out of Thailand reported a 4% mortality rate when they removed the culprit drug, with 84.6% of medications being halted on the first day of hospitalization [51]. Importantly, clinicians should re-evaluate for alternative causative agents if the suspected medication was stopped but symptoms have not improved.

Systemic corticosteroids are generally considered to be the treat- ment of choice for all cases of DRESS [11,49]. Corticosteroids should be initiated when the diagnosis is considered. Data suggest that they are associated with a shortened time to resolution of symptoms (12.5 vs 14.5 days), though there was no difference in mortality [51]. Other case reports and series have demonstrated rapid improvement in symp- toms after initiation of corticosteroids [52,53]. Systemic corticosteroids should be initiated at a minimum dose of 1 mg/kg/day of prednisone or an equivalent corticosteroid with a gradual taper over 3 to 6 months [49,54,55]. Rapid discontinuation of corticosteroids has been associated with early recurrence [23,56]. While the corticosteroids are frequently given orally at the aforementioned dose, pulsed dose methylpredniso- lone (30/mg/kg intravenous daily for three days) can be considered in Refractory cases [23].

Intravenous immunoglobulin (IVIG) given at a dose of 1-2 g/kg for two days can be considered in cases that do not respond to cor- ticosteroids (e.g., systemic symptoms that are worsening or not im- proving after initiation of corticosteroids) [49]. IVIG is proposed to work by replenishing low immunoglobulin levels, protecting against HHV-6, and by direct anti-inflammatory properties [57]. Several case

Table 4

RegiSCAR Criteria for DRESS [8].

Table 5

Shiohara et al. Criteria for DRESS/DIHS47.

      1. maculopapular rash developing >3 weeks after starting with a limited number of drugs
      2. Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug
      3. Fever >38 ?C
      4. Renal or liver abnormalities
      5. Leukocyte abnormalities (at least one present)
        1. Leukocytosis (> 11 x 109/L)
        2. Atypical lymphocytosis (> 5%)
        3. Eosinophilia (> 1.5 x 109/L)
      6. Lymphadenopathy
      7. Human herpesvirus 6 reactivation

DIHS, Drug-Induced Hypersensitivity Syndrome.

The diagnosis is confirmed by the presence of all seven criteria (typical DIHS) or five criteria (atypical DIHS).

reports have demonstrated a benefit with IVIG [58-61], while others have suggested no benefit [62,63]. Therefore, IVIG remains contro- versial but may be considered in refractory cases. However, it is not currently advised as a monotherapy for DRESS in the absence of corticosteroids [62].

Plasmapheresis and immunosuppressive agents (e.g., cyclophospha- mide, cyclosporine, interferons, mycophenolate mofetil, rituximab) may also be considered in refractory cases. Data are limited to isolated case reports demonstrating benefit in cases that did not respond to cor- ticosteroids alone [64-66]. N-acetylcysteine (NAC) has also been re- ported as a potential treatment to aid in detoxification and reduction in reactive metabolites of anticonvulsant-induced DRESS, but the data are similarly limited to case reports [67-69].

  1. Conclusion

DRESS is a hypersensitivity reaction to a drug or its metabolites which can lead to a diffuse inflammatory response. The most commonly affected organ is the skin, but the renal, hepatic, pulmonary, and cardiac systems can also be affected. There are several diagnostic tools available, including the Bocquet, RegiSCAR, and Shiohara criteria. Management includes supportive care, removal of the causative agent, and initiation of systemic corticosteroids. IVIG, immunosuppressants, and NAC may be considered in refractory cases. It is important for emergency clini- cians to be aware of this important and dangerous disease.




Features No Yes Unknown

Fever >38.5 ?C -1 0 -1

Enlarged lymph nodes (>2 sites; >1 cm) 0 1 0

Atypical lymphocytes





700-1499 or 10-19.9%




>=1500 or >= 20%




skin rash Extent >50%

Rash suggestive of DRESS*






Skin biopsy suggestive of DRESS




Internal organ involvement

One 0 1 0

Two or more 0 2 0

Resolution in >=15 days




Exclusion of other causes




A Rash suggestive of DRESS requires >= 2 of the following: purpuric lesions (other than legs), infiltration, facial edema, or psoriasiform desquamation; B Score 1 point if 3 of the following tests were performed and negative: Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Mycoplasma, Chlamydia, Antinuclear antibody, blood culture.

Final score < 2 = not DRESS; 2-3 possible DRESS; 4-5 probable DRESS; >5 definite DRESS.


Author contributions

None except listed

Credit authorship contribution statement

Michael Gottlieb: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Data curation, Conceptualization. Matthew R. Figlewicz: Writing – review & editing, Writing – original draft, Project administration, Data curation. Willeed Rabah: Writing – review & editing, Writing – original draft, Project administration, Data curation. Devon Buddan: Writing – review & editing, Writing – original draft, Project administration, Data curation. Brit Long: Writing – review & editing, Writing – original draft, Project administration, Methodology, Data curation, Conceptualization.

Declaration of Competing Interest



This review does not reflect the views or opinions of the U.S. govern- ment, Department of Defense, U.S. Army, U.S. Air Force, Brooke Army Medical Center, or SAUSHEC EM Residency Program


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