ARTICLE
Auteur(s) :, Jean-Pierre ALLAM1, Teresa
PAUS2, Christoph REICHEL2, Thomas
BIEBER1, Natalija NOVAK1,*
1Department of Dermatology,
Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25 D-53105
Bonn, Germany
2Department of Internal Medicine,
Friedrich-Wilhelms-University, Bonn, Germany
*N Novak, Fax: (+49) 228 287 4881. E-mail:
natalija@uni-bonn.de
accepté le 23 Février 2004
The term “hypersensitivity reaction” refers to a severe,
idiosyncratic cutaneous reaction to drugs, which leads to
long-lasting skin eruptions in combination with lymphadenopathy and
visceral involvement. Drug Rash, Eosinophilia and Systemic
Symptoms, also termed DRESS syndrome, was first introduced in 1996
by Bocquet to decrease the equivocality of the term
“hypersensitivity syndrome” [1]. So far, numerous drugs such as
sulfonamides, nevirapine, phenobarbital, sulfasalazine,
carbamazepine and phenytoin have been reported to cause a DRESS
syndrome [2-6]. Its clinical manifestations include a diffuse
maculopapular rash, exfoliative dermatitis, facial edema,
lymphadenopathy, fever, multivisceral involvement, eosinophilia and
lymphocytosis. It usually appears acutely in the first two months
after initiation of the drug, persists in some cases for months and
is potentially life threatening with a mortality rate of 10% [1].
The incidence of a DRESS syndrome in response to phenytoin,
carbamazepine or phenobarbital treatment is currently about
1/5000 exposures [7].Currently, an association of drug
reactions with Human Herpesvirus 6 infection has been
discussed, although the exact pathophysiological pathway is
unidentified [8]. In most cases, systemic corticosteroid therapy in
combination with the rapid withdrawal of the drug responsible
represents the basic therapeutical principles, even though
randomized clinical trials for the benefit of systemic
corticosteroids are missing [9].
Case report
A 62-year-old patient suffering from epilepsia presented
erythroderma following carbamazepine intake. Prior to this, the
patient had been taken phenytoin for 1/2 year without adverse
reaction. This medication was switched to carbamazepine
12 weeks before the onset of skin eruptions which started one
week before admission with a maculopapular rash on both legs
spreading within days all over the integument, upper extremities
and face (( Fig. 1 )). Later, an
exfoliative dermatitis started to involve both hands (( Fig. 2 )). The patient
also reported simultaneous occurrence of back pain. Clinical
examination disclosed no further abnormal findings. Hematologic and
blood chemical laboratory test results revealed a strong
eosinophilia, leukocytosis, elevated liver enzymes, increased level
of Eosinophil Cationic Protein and hypogammaglobulinemia
(Table I( Table I )). A
histological examination of a skin biopsy revealed a lymphocytic
infiltrate with edema and only a few eosinophils.
On admission the anticonvulsant therapy was switched back from
carbamazepine to phenytoin. Later, we applied systemic steroids
(0.5 mg/kg bodyweight p.o.) daily. The skin eruptions
persisted and the patient started to develop fever accompanied by a
further increase of eosinophils (peak 58.8%) and an abrupt rise of
serum creatinine (peak 2.6 mg/dl [<1.4 mg/dl]). The levels
of leukocytes, CRP and liver enzymes remained elevated. At the same
time a massive diarrhoea occurred. Stool specimens were negative
for infectious agents and a coloscopy was performed to rule out
eosinophilic enterocolitis. Just as in the skin specimen, the
histological examination revealed lymphocytic infiltration with few
eosinophils. At this point all anticonvulsant medication was
discontinued and the skin eruptions finally resolved under
high-dose steroids (1 mg/kg body weight p.o.) application
(Figs 1 and 2). The clinical condition stabilized and the
elevated hematologic and chemical parameters normalized
(Table I). Anticonvulsant therapy was continued with clobazam,
which was well tolerated.
Table I Hematologic and blood chemical laboratory
test results
|
On admission
|
Peak
|
After treatment
|
Standard
|
|
Leukocytes [G/l]
|
22.1
|
25.9
|
13.8
|
4.3-10.5
|
|
Eosinophils [%]
|
33.1
|
54.8
|
1.7
|
< 7
|
|
Neutrophils [%]
|
52.9
|
52.9
|
67
|
19-48
|
|
C-reactive Protein (CRP) [mg/l]
|
123
|
123
|
0.9
|
< 3
|
|
AST [U/l]
|
24
|
30
|
12
|
< 19
|
|
ALT [U/l]
|
61
|
70
|
21
|
< 28
|
|
Gamma-GT [U/l]
|
260
|
270
|
95
|
6-28
|
|
Creatinine (mg/dl)
|
1.1
|
2.6
|
1.3
|
0.5-1.4
|
|
Lactate Dehydrogenase (LDH) 25C [U/l]
|
459
|
459
|
392
|
100-240
|
|
Eosinophil Cationic Protein [μg/l]
|
205
|
205
|
4.02
|
< 4.4
|
|
Gammaglobulins [g/l]
|
1.6
|
1.6
|
9.9
|
6-10
|
Discussion
Patients presenting eosinophilia pose a large number of
differential diagnoses to physicians (Table II( Table II )). Additionally, the diagnostic
procedures often comprise different specialities like general
physicians, dermatologists and pediatrics. Considering
dermatological diseases, a maculopapular rash in combination with
eosinophilia may occur among patients with atopic dermatitis,
hypereosinophilic syndrome (HES), malignancies, eosinophilic
cellulitis (Wells’syndrome) or hypersensitivity reactions to drugs
(Table III( Table III )).
In view of the significant mortality rate of the DRESS syndrome,
which is about 10%, the correct and fast diagnosis of this entity
is of great importance. A detailed medical history – and especially
the history of systemic medications – plays a central role. The
time spread between the initiation of the drug and the onset of
skin eruptions may vary between 2 to 6 weeks up to
2 months [1]. Therefore, it is important to recognize the
initial signs of a DRESS syndrome, especially to avoid any delay in
the withdrawal of the culprit drug. Further hematological findings
besides eosinophilia, like leukocytosis and abnormal blood chemical
test results, just as elevated liver enzymes and serum creatinine
levels, indicate a visceral involvement. The herein reported
hypogammaglobulinemia has been described early in adverse reactions
to anticonvulsants [10]. This is contrary to HES, in which a
hyperglobulinemia can frequently be found [11].
The histological pattern of the skin lesions in DRESS syndrome
sometimes imitates pseudolymphoma but often shows a lymphocytic
infiltrate with few eosinophils, like in this case. The same
histological pattern was found in the bowel specimen of our patient
which was taken to rule out an eosinophilic enterocolitis.
The high ECP levels associated with the massive eosinophilia may
lead to the systemic symptoms as eosinophil-derived protein
toxicity is involved in the development of systemic symptoms in HES
[12, 13]. As reported here for the first time, serum ECP levels may
represent a sufficient parameter to monitor patients developing a
DRESS syndrome and serve as helpful tool to accelerate the
diagnosis. Although the pathological findings of a DRESS syndrome
resolve slowly in general, a possible cross-reactivity between
aromatic anticonvulsants (such as phenytoin, carbamazepine) could
not be excluded in this case and may not only lead to the
development, but also to the worsening of a DRESS syndrome, even
though these drugs have been well tolerated before. Therefore, all
of these drugs should be strictly avoided. Taken together, the
diagnostic and therapeutic challenge of a DRESS syndrome
necessitates interdisciplinary approaches combining the expertise
of dermatologists and other medical disciplines, which are
indispensable for the optimal care of the patient.
Table II Eosinophilic disorders
|
Atopic diseases
|
Atopic eczema, atopic rhinitis, atopic asthma
|
|
Allergy
|
Hypersensitivity reaction
|
|
Malignancies
|
Hodgkin’s disease, myeloproliferative disorders, acute myeloid
leukemia (M4)
|
|
Infections
|
Parasitic infections
|
|
Skin disorders
|
Wells’ syndrome, hypereosinophilic syndrome, eosinophilic
fasciitis
|
|
Pulmonary diseases
|
Churg-Strauss syndrome, eosinophilic pneumonia
|
|
Gastrointestinal disorders
|
Eosinophilic gastroenteritis
|
Table III Differential diagnosis in skin disorders
associated with eosinophilia
|
Medical history
|
Laboratory test
|
Systemic symptoms
|
Skin lesion
|
Skin pathology
|
|
DRESS syndrome
|
Drug initiation or change within the past 2 months
|
Eosinophilia, leukocytosis, elevated liver enzymes, high ECP
levels
|
Liver failure, renal failure, arthralgia, diarrhea
|
Maculopapular rash, exfoliative dermatitis, edema of the face
|
Lymphocytic infiltration, sometimes pseudolymphoma
|
|
HES
|
No association with drugs
|
> 6 months, in some cases leukocytosis, elevated liver
enzymes, high ECP levels
|
Endocarditis, congestive heart failure, thrombosis, strokes,
peripheral neuropathy, encephalopathy, hepatosplenomegaly,
diarrhea, arthralgia
|
Erythroderma, edema, pruritus
|
Eosinophilic infiltration, cutaneous microthrombembolism
|
|
Wells’ syndrome
|
In some cases relation to drugs or insect bite at lesional site
|
> 50% of cases, leukoytosis and thrombocytosis may
occur
|
None
|
Erythema and edema in initial phase, pruritic papular, annular
plaques and urticaria-like eruptions, sometimes vesicles and
blisters
|
Dermal infiltration of eosinophils, initially edema, cell debris
between collagen bundles forming “flame figures”
|
References
1 Bocquet , Bagot , Roujeau Drug-induced pseudolymphoma and
drug hypersensitivity syndrome (Drug Rash with Eosinophilia and
Systemic Symptoms: DRESS) Semin Cutan Med Surg 15 1996 250-257
2 Claudio , Martin , de Dios , Velasco DRESS syndrome
associated with nevirapine therapy Arch Intern Med 161 2001
2501-2502
3 Bourezane , Salard , Hoen , Vandel , Drobacheff ,
Laurent DRESS (drug rash with eosinophilia and systemic symptoms)
syndrome associated with nevirapine therapy Clin Infect Dis 27 1998
1321-1322
4 Lachgar , Touil The drug hypersensitivity syndrome or
DRESS syndrome to phenobarbital Allerg Immunol 33 2001 173-175
5 Lanzafame , Rovere , De Checchi , Trevenzoli ,
Turazzini , Parrinello Hypersensitivity syndrome (DRESS) and
meningoencephalitis associated with nevirapine therapy Scand J
Infect Dis 33 2001 475-476
6 Queyrel , Catteau , Michon-Pasturel , et-al.
DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome
after sulfasalazine and carbamazepine: report of two cases Rev Med
Interne 22 2001 582-586
7 Case records of the Massachusetts General Hospital.
Weekly clinicopathological exercises. Case 26-1996. A
seven-year-old boy with fever, lymphadenopathy, hepatosplenomegaly,
and prominent eosinophilia N Engl J Med 335 1996 577-584
8 Descamps , Valance , Edlinger , et-al.
Association of human herpesvirus 6 infection with drug
reaction with eosinophilia and systemic symptoms Arch Dermatol 137
2001 301-304
9 Tas S, Simonart T. Drug rash with eosinophilia and
systemic symptoms (DRESS syndrome). Acta Clin Belg, 54:
197-200.
10 Travin , Macris , Block , Schwimmer Reversible common
variable immunodeficiency syndrome induced by phenytoin Arch Intern
Med 149 1999 1421-1422
11 Weller , Bubley The idiopathic hypereosinophilic
syndrome Blood 83 1994 2759-2779
12 Rauch , Amyot , Dunn , Ng , Wilner Hypereosinophilic
syndrome and myocardial infarction in a 15-year-old Pediatr Pathol
Lab Med 17 1997 469-486
13 Foong , Scholes , Gleich , Kephart , Holt
Eosinophil-induced chronic active hepatitis in the idiopathic
hypereosinophilic syndrome Hepatology 13 1991 1090-1094
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