The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–4, 2011
Copyright Ó 2011 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/$ - see front matter
doi:10.1016/j.jemermed.2011.05.052
Clinical
Communications: Adults
PHENYTOIN-INDUCED DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC
SYMPTOMS (DRESS) SYNDROME: A CASE REPORT FROM THE
EMERGENCY DEPARTMENT
Lindsay L. Oelze, MD* and M. Tyson Pillow, MD*†
*Baylor College of Medicine, Houston, Texas and †Department of Medicine, Section of Emergency Medicine, Ben Taub General Hospital,
Houston, Texas
Reprint Address: Lindsay L. Oelze, MD, Department of Medicine, Section of Emergency Medicine, Ben Taub General Hospital, 1504 Taub
Loop, EM Academic Offices, Houston, TX 77030
, Abstract—Background: Drug rash with eosinophilia
and systemic symptoms (DRESS) syndrome is an uncommon but serious hypersensitivity drug reaction most
frequently associated with antiepileptics. Clinical manifestations include rash, fever, and visceral organ involvement,
most commonly hepatitis. The mortality rate associated
with DRESS syndrome is approximately 10%, the majority
due to fulminant liver failure. Objectives: We report one
case of phenytoin-induced DRESS syndrome in a patient
who presented to the Emergency Department (ED). Our
objectives for this case report include: 1) to learn the importance of DRESS syndrome; 2) to recognize the signs and
symptoms of DRESS syndrome; 3) to know what diagnostic
studies are indicated; and 4) to learn the appropriate
treatment. Case Report: We report one case of phenytoininduced DRESS syndrome in a 34-year-old man, previously
on phenytoin for seizure prophylaxis, who presented to the
ED with 5 days of worsening symptoms including generalized rash, fever, tongue swelling, and dysphagia. Laboratory
results revealed an eosinophilia and elevated liver enzymes.
With initiation of steroids, the transaminitis improved
despite increasing eosinophilia and development of an atypical lymphocytosis. Fever and angioedema resolved with
improvement of the rash, and the patient was discharged
on hospital day 3. Conclusion: Given the significant
mortality related to DRESS syndrome, ED staff should
have a low threshold for suspecting the condition in patients
who present with unusual complaints and skin findings after
starting any antiepileptic drug. Early diagnosis and prompt
treatment with corticosteroids is imperative.
Elsevier Inc.
Ó 2011
, Keywords—DRESS syndrome; phenytoin; drug reaction; hypersensitivity reaction; antiepileptic-induced hypersensitivity reaction
INTRODUCTION
Drug rash with eosinophilia and systemic symptoms
(DRESS) syndrome was first described in 1959 associated with phenytoin and was previously referred to as
drug-induced pseudolymphoma (1). It is characterized
by skin rash, fever, pharyngitis, lymphadenopathy, and
visceral organ involvement, typically presenting within
8 weeks of initiation of therapy. This reaction can be
life threatening, with a mortality rate of approximately
10%, most commonly secondary to liver failure (2).
The exact incidence of DRESS syndrome is unknown,
but it is estimated to occur in at least 1 per 1500 new users
of phenytoin and carbamazepine (3). A majority of reported cases are African-American males (2). Typically,
fever precedes the development of a diffuse, morbilliform
rash that can advance to an exfoliative dermatitis. According to a recent observational study of 24 patients
with DRESS syndrome, all presented with rash and fever,
RECEIVED: 4 October 2010; FINAL SUBMISSION RECEIVED: 15 November 2010;
ACCEPTED: 23 May 2011
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L. L. Oelze and M. T. Pillow
50% with abnormalities on complete blood count (CBC)
including eosinophilia (> 500/uL) or presence of atypical
lymphocytes, > 90% with hepatitis, 60% with localized or
generalized edema, 33% with lymphadenopathy, and
30% with pharyngitis (4). Other organs can be involved
leading to interstitial nephritis, myocarditis, pneumonitis,
and rarely, meningoencephalitis (2). When a patient
presents to the Emergency Department (ED) with skin
findings and unusual complaints after starting any new
drug, particularly antiepileptics, physical examination
and appropriate diagnostic testing should be performed
to detect systemic involvement. Initial testing should
include a CBC with differential and peripheral smear,
liver panel, serum creatinine, chest X-ray, and urinalysis.
CASE REPORT
A 34-year-old African-American man presented to the
ED complaining of a 5-day history of generalized pruritic, morbilliform rash associated with fever to 39.4 C
(103 F), tongue swelling, and dysphagia. He had undergone craniotomy 16 days prior to presentation for resection of an anaplastic astrocytoma at an outside facility.
The patient had been loaded with fosphenytoin at the
time of surgery and transitioned to oral phenytoin. He
had been on phenytoin for just over 2 weeks when symptoms began. Three days before arrival in the ED, he had
been seen at an outside hospital for the same complaints
and phenytoin was replaced with levetiracetam. The
symptoms worsened despite discontinuation of phenytoin
prompting the patient to again seek care in the ED. Medications at the time of presentation included levetiracetam
2000 mg orally (p.o.) twice a day (b.i.d.), dexamethasone
4 mg p.o. b.i.d. (since craniotomy), lisinopril 5 mg p.o.
daily, and acetaminophen. Review of systems was negative for cough, prior rash, joint pain, or any other contributing symptoms. He denied any known drug allergies,
other past medical history, and alcohol use. He did have
a 10 pack-year smoking history. On examination, the patient was febrile to 38.7 C (101.6 F), with a pulse of
96 beats/min and a blood pressure of 120/59 mm Hg.
The patient was alert and fully oriented, appearing uncomfortable, but non-toxic. A diffuse, blanching erythema
was noted involving the face, trunk, and extremities without
desquamation (Figures 1–3). There was no involvement of
the oral mucosa, palms, or soles. Nikolsky test was
negative. There was angioedema of the lips and tongue
without airway compromise. No erythema or exudate was
noted upon examination of the posterior pharynx. No
lymphadenopathy was appreciated, and breath sounds
were clear to auscultation bilaterally with a regular rate
and rhythm on cardiovascular examination. There was
no organomegaly or abdominal tenderness. Neurologic
examination was non-focal, with no deficits noted.
Figure 1. Diffuse erythematous rash on the arm of a patient
who presented with DRESS syndrome.
Laboratory results revealed a normal white blood cell
count of 9.8 with 81% neutrophils and 7% eosinophils or
0.69 K/uL abs eosinophils (normal 0–3%). The patient
also was noted to have a transaminitis with alanine aminotransferase (ALT) of 131 U/L (normal 30–65 U/L), aspartate
aminotransferase (AST) of 387 U/L (normal 15–37 U/L),
and alkaline phosphatase of 198 U/L (normal 50–136). A
phenytoin level was 5.4 (therapeutic 10–20) and basic
Figure 2. Diffuse erythematous rash on the leg of a patient
who presented with DRESS syndrome.
DRESS Syndrome
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Figure 3. Diffuse erythematous rash on the back of a patient
who presented with DRESS syndrome.
metabolic panel was unremarkable. A hepatitis panel and
abdominal ultrasound were negative. A chest X-ray
revealed mild perihilar prominence with peribronchial
thickening. The patient was admitted with a diagnosis of
DRESS syndrome. Dexamethasone was increased to
4 mg p.o. four times a day and levetiracetam was continued at the same dose and frequency. On hospital day 1,
transaminases worsened, with ALT of 602, AST of 211,
and alkaline phosphatase of 245. Repeat CBC showed improvement in the eosinophilia to 3%, but an atypical
lymphocytosis of 10% with white blood cell (WBC) count
of 11.8. Lisinopril was discontinued due to possibility
of contribution to the angioedema.
On hospital day 2, the transaminitis showed improvement, but CBC demonstrated an increase in atypical lymphocytes to 31%, in addition to an absolute eosinophil
count of 0.7 K/uL with 3% eosinophils on differential.
All symptomatology was resolving. On hospital day 3,
the transaminases had continued to improve to 475 and
84 for ALT and AST, respectively. An increased atypical
lymphocytosis was noted to 45% on differential, with
a WBC count of 34. Absolute eosinophils increased to
2.39 with 7% eosinophils. Because the patient’s symptoms had continued to improve with resolution of fever
and angioedema, he was discharged home on hospital
day 3 on continued dexamethasone and levetiracetam
with close follow-up with Oncology.
DISCUSSION
Although most commonly associated with phenytoin,
carbamazepine, and phenobarbital, DRESS syndrome
has also been reported after exposure to a myriad of medications including lamotrigine, oxcarbazepine, vancomycin, sulfasalazine, doxycycline, allopurinol, linezolid,
nitrofurantoin, atorvastatin, and esomeprazole (2,5–12).
Interestingly, the first case of DRESS syndrome related
to levetiracetam was described just last year (13). Most
cases of DRESS syndrome occur within 8 weeks of
exposure, but one case report occurred 4 months after
initiation of carbamazepine (14).
Although formal diagnostic guidelines have not been
formed, Bocquet et al. proposed the following three absolute criteria for diagnosis: 1) cutaneous drug eruption, 2)
eosinophilia > 1.5 109/L or presence of atypical lymphocytes, and 3) systemic involvement indicated by adenopathies > 2 cm in diameter, hepatitis, interstitial nephritis,
interstitial pneumonitis, or carditis (2). More recently,
a Japanese consensus group established a revised set of
diagnostic criteria requiring all seven of the following:
1) maculopapular rash developing > 3 weeks after starting a limited number of drugs, 2) prolonged clinical
symptoms 2 weeks after discontinuation of the causative
drug, 3) fever, 4) liver abnormalities (ALT > 100), 5) leukocyte abnormalities (leukocytosis > 11 109/L , atypical lymphocytes > 5%, or eosinophilia > 1.5 109/L), 6)
lymphadenopathy, and 7) human herpes virus 6 reactivation (15). The last criteria refers to more recent but
controversial evidence that DRESS syndrome may be
caused by a reactivation of or new infection with human
herpes virus 6 (15).
CONCLUSION
When DRESS syndrome is in the differential diagnosis,
one should also consider other dangerous causes of severe
cutaneous drug reaction such as Stevens-Johnson syndrome and toxic epidermal necrolysis. These typically
occur sooner after drug exposure than does DRESS syndrome, within 1–3 weeks. The systemic symptoms and
eosinophilia are also useful distinguishing characteristics,
as is the absence of Nikolsky sign with DRESS syndrome.
Other serious causes of a diffuse rash with signs of systemic involvement include staphylococcal scalded skin
syndrome and, in the pediatric population, Kawasaki disease. Benign etiologies in the differential include mononucleosis with viral exanthem and simple drug reaction.
When a patient presents to the ED with signs and
symptoms concerning for a hypersensitivity reaction,
a thorough drug history should be obtained, including
drugs started up to 6 months before presentation. A careful examination should be performed looking for lymphadenopathy, edema, and hepatomegaly. Initial laboratory
evaluation should include a comprehensive metabolic
panel with liver enzymes, complete blood count with
differential and peripheral smear, chest X-ray, and
urinalysis. The liver enzymes should be followed for
improvement, as the most common cause of mortality
in patients with DRESS syndrome is hepatic failure (2).
Although there are no published admission criteria,
patients with DRESS syndrome should be admitted if
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L. L. Oelze and M. T. Pillow
there is concern for worsening liver enzymes, or if there
are other laboratory abnormalities indicative of systemic
involvement that need to be trended, such as an elevated
creatinine with concern for acute renal failure secondary
to interstitial nephritis. Certain abnormal findings on physical examination would also warrant admission and close
observation, such as angioedema or altered mental status.
The mainstay of treatment consists of corticosteroids,
often producing rapid improvement in symptomatology
(5). Supportive therapy includes antipyretics, antihistamines, topical steroids, and topical moisturizers. Relapse
is possible with repeat exposure to the offending drug
and when steroids are tapered or discontinued (5). Family
members of the patient should be counseled as DRESS
syndrome has been described in familial aggregations (2).
In conclusion, DRESS syndrome is a severe hypersensitivity reaction that has been implicated with numerous
drugs. Early diagnosis and prompt treatment with corticosteroids is imperative. Emergency physicians should
consider DRESS syndrome when evaluating patients
who present with skin rash and unusual or systemic
complaints in association with any new medication,
particularly antiepileptics.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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