ARTICLE
Auteur(s) : Todor Petkov, Georgy Pehlivanov, Ivan
Grozdev, Svetlana
Kavaklieva, Nikolai Tsankov
Medical Faculty, Department of Dermatology and Venereology,
1st Georgy Sofiyski str., Sofia 1431, Bulgaria
accepté le 17 Avril 2007
Drug hypersensitivity syndrome is an adverse drug reaction
associated mainly with the aromatic antiepileptic drugs phenytoin,
carbamazepine and phenobarbital [1]. The relatively new
antiepileptic drug lamotrigine is also reported to cause DHS [2-4].
The syndrome can also be caused by a variety of other drugs, such
as sulfonamides [5], dapsone [6], minocylcine [7], terbinafine [8],
azathioprine [9], and allopurinol [10]. It is usually defined by
the triad of fever, skin rash and symptomatic or asymptomatic
internal organ involvement [1]. The organs most commonly affected
are liver, kidney and lungs. Hematological changes such as
leucocytosis, eosinophilia and lymphocytosis are also frequently
observed. Anticonvulsant hypersensitivity syndrome (AHS) was first
described by Chaiken et al. in 1950 [11]. Bocquel et al. recently
proposed the acronym DRESS for ‘Drug Rash with Eosinophilia and
Systemic Symptoms’ to refer to AHS, but no consensus has yet been
reached for its use [12]. We report 3 cases of DHS where the
causative agents were lamotrigine (case 1), salazopyrine (case 2)
and carbamazepine (case 3).
Case 1
A 32-year-old man had been taking Depakine® (valproic
acid) for 15 years due to epilepsy. Lamotrigine 25 mg/d was
added to the therapy because of persisting locomotive seizures. One
week later on 16.10.2004, the patient developed a facial edema,
pain in the throat and formication of the toes. The symptoms
persisted despite the application of corticosteroids and
antihistamines. Five days later the patient was shivering with
wide-spread erythema. He felt a burning pain in his feet and it was
impossible for him to step and walk. There were ulcerations in the
oral cavity.
Physical examination showed a febrile condition (39 °C),
bilateral submandibular lymphadenopathy, tachycardia (130
beats/min), decreased blood pressure 105/60mmHg, and
hepatosplenomegaly. Soon after the admission a massive peeling of
the skin of the face, trunk and extremities appeared (figure 1). The body
surface area (BSA) detachment was above 30%, which was estimated by
the rule of nine. Hemorrhagic blisters were seen on the hands and
feet. Widespread erosions on the oral and genital mucosa appeared
and hemorrhagic crusts covered the lips. Vision was impaired by the
purulent exudation and conjunctival reaction. The sign of Nickolsky
was positive. Laboratory findings showed increased erythrocytes
sedimentation rate and liver enzymes, as well as peripheral blood
eosinophilia (10%, 1.53 × 109/L, NR 0-0.5 ×
109/L). The low pO2 and elevated levels of
pCO2 were coherent with the picture of slight
respiratory failure. The dynamic of liver enzymes during the course
of therapy is shown in table 1.
Microbiology swabs from the skin isolated Candida spp. and E. coli
from the oral cavity. Examination of sterile urine was
negative.
The biopsy specimen from a lesion showed total necrosis and
complete separation of the epidermis from the underlying dermis,
suggesting toxic epidermal necrosis (figure 2). Scant
perivascular infiltrate in the upper dermis was noted. Nearly all
epidermal structures were obliterated.
Table 1 Change of liver enzymes during the treatment of
the patient
|
Liver enzymes
|
|
|
Date
|
ASAT NR 5-40 U/L
|
ALAT NR 5-40 U/L
|
GGT NR 5-50 U/L
|
TB NR < 21 mmol/L
|
CPK NR < 80 U/L
|
|
28.10.2004
|
29
|
40
|
20
|
13
|
38
|
|
29.10.2004
|
41
|
48
|
23
|
13
|
|
|
30.10.2004
|
26
|
50
|
|
10.2
|
|
|
31.10.2004
|
21
|
50
|
48
|
4.6
|
257
|
|
11.11.2004
|
19
|
21
|
35
|
3.8
|
58
|
|
08.12.2004
|
18
|
15
|
76
|
5.6
|
78
|
Case 2
A 32-year-old man who had been suffering from inflammatory bowel
disease was treated with salazopyrine 1,500 mg/d and
omeprazole 20 mg/d. Thirteen days after the therapy initiation
on 20.06.2005, he developed an erythematous maculo-papulous rash on
the photo-exposed skin areas. After 2 days the skin condition
worsened with the appearance of flaccid blisters and diffuse
erosions on erythematous macules with poorly defined borders over
the face, body and extremities (figure 3). The overall
body surface affected by blisters and erosions was approximately
30%. The sign of Nikolsy was found positive. Erosions of the oral,
nasal and genital mucosa were noted. Severe conjunctival
involvement with exudation was present. At admission the patient
was febrile up to 39 °C.
Initial laboratory investigations suggested strong inflammatory
reactions and liver dysfunction: elevated ESR, leucocytosis (20 ×
109/L, NR 3.5-10.5 × 109/L) with eosinophilia
(2 × 109/L, NR 0-0.5 × 109/L), elevated liver
enzymes: ASAT 80 IU/L (NR 5-40 U/L), ALAT 67 IU/L (NR 5-40 U/L),
GGT 155 IU/l (NR 5-50 U/L). Microbiological examination of
cutaneous swabs revealed Staphylococcus haemolyticus and
Streptococcus epidermidis. Acinetobacter baumanii was isolated from
the oral cavity. Histopathological examination of lesional skin
showed complete absence of the epidermis and predominantly
perivascular infiltrate (figure 4).
Case 3
A 28-year-old man with long history of alcohol abuse started
therapy with carbamazepine 600 mg/d, diazepame 10 mg/d
and clonidine 0.30 mg/d. After 10 days he had concomitant
excessive alcohol intake and 2 days later, on 09.01.2006, the
patient complained of weakness, joint pain and fever up to
40 °C. The skin was covered with small erythematous macules
which quickly became confluent forming large scalded areas
especially on the face and neck (figure 5). Large
hemorrhagic blisters were formed on the palms and soles as the
disease progressed. Nikolsy’s sign was positive. Above 30% of BSA
detachment was evaluated. Conjunctivitis without corneal erosions
was proven by the ophthalmology consultation. The lips were covered
with hemorrhagic crusts and erosions of oral and genital mucosa
were present. There was significant hepatosplenomegaly (3.5 cm
below the rib arch).
At admission the patient was in poor general health, somnolent
and disoriented. Auscultation of the lungs revealed wet whistles at
the base; tachycardia (110 beats/min) and decreased blood pressure
110/70mmHg. Laboratory investigations revealed elevated ESR, liver
enzymes, CPK and leucocytosis (12.5 × 109/L, NR 3.5-10.5
× 109/L) with eosinophilia (12%, 1.5 × 109/L,
NR 0-0.5 × 109/L). The laboratory findings showed
considerable changes during treatment (table
2). There was a pulmonary involvement – pneumonia and H.
Infuenzae was cultured from a sputum specimen.
A biopsy specimen from the lesion was taken which showed
necrosis and separation of the epidermis from the underlying
dermis. Intensive mononuclear infiltrate in the upper dermis was
noted (figure
6).
At admission of all three patients the culprit drug was
discontinued and life-saving measures were taken immediately –
infusion of 4,000 mL/d, monitoring and control of vital signs.
Systemic methylprednisolone at an initial dose of 2 mg/kg/d
was started as well as broad spectrum systemic antibiotics –
cephalosporins 2nd or 3rd generation. Locally
the patients received dressings and spraying of Avène thermal
water. Antimycotics and ophthalmic drugs were also included in the
3 cases. After the hospital treatment the patient 1 had improvement
of the dermatological condition in 6 weeks and was discharged on
10.12.2004. Patients 2 and 3 showed quicker resolution and were
discharged from the department on 23.07.2005 patient 2 and patient
3 on 31.01.2006.
On the follow-up visit 1 month after treatment all the patients
had nail manifestations: total loss of the nail plate or transverse
nail striation. Defluvium of the scalp was present. Cases 1 and 2
suffered from disabling late complications such as total loss of
eyelashes of the lower eyelids with subsequent growth to the bulbar
conjunctiva and damaging the corneal epithelium. On the follow-up
visit 3 months later patient 2 had symptoms of hypothyroidism with
elevated TSH and decreased T3, T4 and the
patient was given a substitution therapy.
Table 2 During the therapy course liver enzymes
decreased considerably
|
Liver enzymes
|
Urinalysis
|
|
|
Date
|
ASAT NR 5-40 U/L
|
A LAT NR 5-40 U/L
|
GGT NR 5-50 U/L
|
TB NR < 21 mmol/L
|
Protein
|
Urobil
|
Sediment
|
CPK NR < 80 U/L
|
|
09.01.2006
|
66
|
98
|
393
|
15.3
|
(+)
|
Elevated
|
Er 10-12, Leuc 14-15, Bacteria
|
392
|
|
13.01.2006
|
27
|
50
|
374
|
16.3
|
(–)
|
Normal
|
Er 1-2, Leuc 1-2
|
|
|
17.01.2006
|
26
|
50
|
251
|
21.2
|
(+)
|
Normal
|
Er 2-3, Leuc 25-30
|
|
|
24.01.2006
|
14
|
55
|
130
|
7.4
|
(+)
|
Normal
|
Er 3-4, Leuc 20-30
|
|
Discussion
The incidence of the syndrome is unclear because its variable
presentation, diverse clinical features and laboratory
abnormalities have led to inaccurate reporting [13]. It has been
estimated that the incidence of life-threatening skin reactions due
to lamotrigine may occur in up to 1/1,000 adults and 1/50-100
children [14]. DHS starts within the first 2-8 weeks after the
initial drug exposure. The reaction usually begins with low- or
high-grade fever, and over the next 1-2 days a cutaneous eruption,
lymphadenopathy, and pharyngitis may develop. This is followed by
involvement of various internal organs, most commonly the liver,
kidney and lungs [13]. Hematological abnormalities are also very
common. The most prominent organ manifestations are hepatitis,
eosinophilia, blood dyscrasias, and nephritis [1]. Presence of
three of these criteria establishes the diagnosis [12]. Additional
clinical and laboratory findings may include periorbital or facial
edema, exudative tonsillitis, oral ulcers, strawberry tongue,
hepatosplenomegaly, flu-like symptoms, myopathy, disseminated
intravascular coagulopathy, pneumonitis, colitis. The reported case
2 developed symptoms of hypothyroidism which is also part of the
hypersensitivity syndrome. The literature sources confirm cases of
thyroid involvement due to anticonvulsants and sulfonamides
[15-17].
The skin rash is most commonly an exanthema with or without
pruritus. Rarely, generalized follicular pustules or more severe
skin reactions, such as exfoliative dermatitis, Stevens-Johnson
syndrome (SJS) or toxic epidermal necrolysis (TEN) may occur. The
incidence of these severe skin reactions as part of AHS was found
to be as high as 9% among 53 patients with AHS induced by
phenytoin, carbamazepine or phenobarbital reported by Shear and
Spielberg [18]. Angioedema (especially facial or periorbital
swelling) may be a sign of a systemic and potentially severe
life-threatening reaction.
The liver is the most frequently involved internal organ in DHS
and the rate in reported patients ranges from 34% to 94%. The organ
involvement can vary from mild elevations in liver enzymes, to
marked abnormalities in function tests with hepatomegaly, and
fulminant hepatic necrosis [19]. All three patients had elevated
liver enzymes, but the most prominent changes were seen in case 3
who had concomitant alcohol liver damage. It was not clear if the
alcohol intake had an impact as a trigger or enhancing factor for
the occurrence of the hypersensitivity syndrome.
Laboratory features of the syndrome are leukocytosis with
eosinophilia and atypical lymphocytosis. The latter was not found
in the cases described. Other laboratory abnormalities include
agranulocytosis, aplastic anemia, hemolytic anemia,
thrombocytopenia and hypogammaglobulinemia. Boccara et al.
demonstrated in a retrospective study that hypogammaglobulinemia is
frequent in DRESS and less frequent in other causes of erythroderma
and this transient immune dysfunction is probably a consequence of
a severe B cell depletion observed at the beginning of the DRESS.
Further prospective studies are necessary to confirm the
association of hypogammaglobulinemia with DRESS [20].
The complete pathogenesis of DHS is unknown. There is evidence
suggesting that AHS induced by phenytoin, carbamazepine or
phenobarbital is associated with a relative excess of reactive
toxic metabolites due to absence or mutation of enzyme epoxide
hydroxylase [18]. Defective detoxification may lead to cell death
or contribute to the formation of an antigen that triggers an
immune reaction [18]. In the recent years the hypothesis was
proposed regarding the role of human herpesvirus – 6 (HHV-6) in the
pathogenesis of DHS [21-24]. According to this assumption the
extent of T-cell response to the viral reactivation of HH-6 is
responsible for the extent of organ and skin changes [23]. Some
other authors state that it is not clear what determines the
severity of the reaction and the clinical phenotype, i.e. the
nature and extent of organ involvement, although genetic factors
may be important. Indeed, even first degree relatives of patients
should be asked to avoid similar drugs [25].
In differential diagnosis, other cutaneous drug reactions, acute
infections (Epstein-Barr virus, viral hepatitis A and B,
Streptococcus), lymphoma or pseudolymphoma, collagen vascular
diseases and serum sickness-like reaction should be kept in mind.
Although lymphocyte transformation tests and epicutaneous tests can
be used, the diagnosis is usually made based on time of onset,
clinical and laboratory examination and resolution with cessation
of the offending drug [26].
In terms of clearly elucidating the differentials between
erythema multiforme, Stevens-Johnson syndrome and toxic epidermal
necrolysis, a classification based on the pattern of erythema
multiforme-like lesions and on the extent of epidermal detachment
has been proposed [27]. According to the criteria of this
classification the diagnosis of TEN was made in the three cases as
none of them presented with typical targets and the BSA detachment
was 30% and more.
Controversy regarding classification of DHS and SJS/TEN exists
and there are some arguments for not including patients with
SJS/TEN in DHS [28]. Still the kind of rash is not clearly
indicated in the definition of the DHS, which enables many authors
to classify cases with SJS/TEN as a ‘DHS with severe cutaneous
reactions’, when other characteristics fit into the definition. In
our cases the differential diagnosis of DHS and TEN is based on the
presence of fever, lymphadenopathy, liver involvement in the 3
cases and in addition pulmonary involvement in case 1, as well as
peripheral blood eosinophilia (≥ 1.5 × 109/L). On
the other hand, the patients had the following distinguishing
features: (i) quick withdrawal of the skin lesions after cessation
of the culprit drug, (ii) better course of the disease, (iii) very
good response to systemic corticosteroids.
Treatment is primarily symptomatic but regarding the fact that
some patients are in a life-threatening situation the therapy must
be started immediately with hospital admission and including all
necessary life-support measures. The efficacy of corticosteroids is
debatable, but some authors recommend the use of prednisone at a
dosage of 1-2 mg/kg/day if symptoms are severe [29]. In general, a
corticosteroid regimen produces a favorable response, as was
notably confirmed with our 3 patients. In other patients, signs of
deterioration or relapse may be observed despite medication, over a
long period of time [1]. One should be cautious regarding local
measurements as most of the local antiseptics and antibiotics could
have sensitizing potential. Silver sulfadiazine is not usually
recommended in cases of toxic epidermal necrolysis because it has
been reported to cause leucopenia and sulfonamides are associated
with severe cutaneous adverse reactions [30]. Our patients
tolerated the application of Avène thermal water spray at the acute
phase of the disease very well. The topical application of
Dermocare® in all three patients gave some very
promising results regarding the softening of inflammation and skin
recovery.
Patients who are re-challenged with the culprit medication,
whether inadvertently or in a controlled setting, develop the
symptoms of fever, skin rash and lymphadenopathy almost immediately
after re-exposure. The incidence of cross-reactivity among the
aromatic anticonvulsants: carbamazepine, phenytoin, phenobarbital,
which share an arene oxide intermediary, is greater than 75% [1].
Even though cases of AHS due to lamotrigine have been reported in
the literature, cross-reactivity between aromatic anticonvulsants
and lamotrigine has not been demonstrated to date [30]. In case 2
we consider salazopyrine as the offending drug of the DHS, but
omeprazole was also administered and suspected. Omeprazole has not
been reported in the literature to cause DHS, but cases of
omeprazole-induced TEN have been recently published [31].
Conclusion
We present three cases of DHS caused by different medications
(anticonvulsants and sulfonamide). All patients were in
life-threatening conditions. Withdrawal of the culprit drug is
essential as it leads to quick improvement. In the literature,
cases with TEN as a feature of DHS have been published [32-34]. The
internal organ involvement of the patients with DHS included the
liver, lungs and thyroid gland. The patients had hematological
abnormalities comprising of leucocytosis with eosinophilia. They
were successfully treated with a combination of broad spectrum
antibiotics and corticosteroids in moderate doses, which were
quickly tapered with improvement of the patients. The topical
therapy included dressings, thermal water spray,
Dermocare® (Sunflower seed oil amphoglycinate), etc. The
considerable improvement was seen in 3 to 6 weeks after the therapy
initiation. All patients obtained very good results and tolerated
the topical application of thermal water spray (Avène) 6 to 8 times
per day very well. In the follow-up period of more than 1.5 years
the patients remain in good condition and have had no new episodes
of aggravation.
Acknowledgements
Financial support: None. Conflict of Interest: None.
References
1 Handfield-Jones SE, Jenkins RE, Whittaker SJ,
Besse CP, McGibbon DH. The anticonvulsant
hypersensitivity syndrome. Br J Dermatol 1993; 129: 175-7.
2 Schaub N, Bircher AJ. Severe hypersensitivity
syndrome to lamotrigine confirmed by lymphocyte stimulation in
vitro. Allergy 2000; 55: 191-3.
3 Sullivan JR, Neuman IM, Snear HN. The drug
hypersensitivity syndrome and Lamotrigine. Aust J Dermatol 2001;
42(suppl. 1): A23.
4 Deandel PY, Traisac T, Rainfray M, et al.
Drug hypersensitivity Syndrome with Lamotrigine two cases in
elderly. Press Med 2005; 34(7): 516-8.
5 Rieder MJ, Uetrcht J, Shear NH, Cannon M,
Miller M, Spielberg SP. Diagnosis of sulfonamide
hypersensitivity reactions by in-vitro ‘rechallenge’ with
hydroxylamine metabolites. Ann Intern Med 1989; 110: 286-9.
6 Prussick R, Shear NH. Dapsone hypersensitivity
syndrome. J Am Acad Dermatol 1996; 35: 346-9.
7 Knowles SR, Shapiro L, Shear NH. Serious
adverse drug reactions induced by minocycline. Report of 13
patients and review of the literature. Arch Dermatol 1996; 132:
934-9.
8 Gupta AK, Kopstein JB, Shear NH.
Hypersensitivity reaction to terbinafine. J Am Acad Dermatol 1997;
36: 1018-9.
9 Knowles SR, Gupta AK, Shear NH, Sauder S.
Azathioprine hypersensitivity-like reactions – a case report and
review of the literature. Clin Exp Dermatol 1995; 20: 353-6.
10 Arellano F, Sacristan JA. Allopurinol
hypersensitivity syndrome: a review. Ann Pharmacother 1993; 19:
337-43.
11 Chaiken BH, Goldberg BI, Segal JP. Dilantin
sensitivity; report of a case of hepatitis with jaundice, pyrexia
and exfoliative dermatitis. N Engl J Med 1950; 242(23): 897-8.
12 Bocquel H, Bagot M, Roujeau JC. Drug induced
pseudolymphoma and drug hypersensitivity (drug rash with
eosinophilia and systemic symptoms). Semin Cutan Med Surg 1996; 15:
250-5.
13 Vittorio CC, Muglia JJ. Anticonvulsant
hypersensitivity syndrome. Arch Intern Med 1995; 155: 2285-90.
14 Fattinger K, Roos M, Vergeres P, et al.
Epidemiology of drug exposure and adverse drug reactions in two
Swiss departments of internal medicine. Br J Clin Pharmacol 2000;
49: 158-67.
15 Teo YL, Tay YK, Tan CH, et al. Presumed
Dapson – induced drug hypersensitivity syndrome causing reversible
hypersensitivity myocarditis and thyrotoxicosis. Ann Acad Med 2006;
35(11): 833-6.
16 Kaminski A, Moreno M, Diaz M, et al.
Anticonvulsant hypersensitivity syndrome. Int J Dermatol 2005; 44:
594-8.
17 Gupta A, Eggo M, Uetrecht J, et al.
Drug-induced hypothyroidism: the thyroid as a target organ in
hypersensitivity reactions to anticonvulsants and sulfonamides.
Clin Pharmacol Ther 1992; 5: 56-67.
18 Shear NH, Spielberg SP. Anticonvulsant
hypersensitivity syndrome: in vitro assessment of risk. J Clin
Invest 1988; 82: 1826-32.
19 Syn WK, Naibitt DJ, Holt AP,
Pirmohamed M, Mutimer DJ. Carbamazepine-induced acute
liver failure as part of the DRESS syndrome. Int J Clin Pract 2005;
59(8): 988-91.
20 Boccara O, Valeyrie-Allanore L, Crickx B,
Descamps V. Association of hypogammaglobulinemia with DRESS
(Drug Rash with Eosinophilia and Systemic Symptoms). Eur J Dermatol
2006; 16(6): 666-8.
21 Kano Y, Inaoka M, Shiohara T. Association
between anticonvulsant hypersensitivity syndrome and human
herpsevirus 6 reactivation and hypergammaglobulinemia. Arch
Dermatol 2004; 140: 183-8.
22 Tohyama M, Yahata Y, Yasukama H, et al.
Severe hypersensitivity syndrome due to sulfasalazine associated
with reactivation of human herpsevirus 6. Arch Dermatol 1998; 134:
1113-7.
23 Suzuki Y, Ihagi R, Aono T. Human herpesvirus
infection as a risk factor for the development of severe drug
induced hypersensitivity syndrome. Arch Dermatol 1998; 134:
1108-12.
24 Descanp V, Valance A, Edlinger C, et al.
Association of human herpesvirus 6 infection with drug reaction
with eosinophilia and systemic symptoms. Arch Dermatol 2001; 137:
301-6.
25 Rzany B, Correia O, Kelly JP, Naldi L,
Anquier A, Stern R. Risk of Stevens-Johnson syndrome and
toxic epidermal necrolysis during first weeks of antiepileptic
therapy: a case-control study. Study group of the International
Case Control Study on Severe Cutaneous Adverse Reactions. Lancet
1999; 353: 2190-4.
26 Jones M, Fernandez-Herrera J, Dorado JM,
et al. Epicutaneous test in carbamazepine cutaneous reactions.
Dermatology 1994; 188: 18-20.
27 Bastuji-Garin S, Rzany B, Stern R, et al.
Clinical classification of cases of toxic epidermal necrolysis,
Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol
1993; 129: 92-6.
28 Wolf R, Matz H, Marcos B, Orion E. Drug
rash with eosinophilia and systemic symptoms vs toxic epidermal
necrolysis: the dilemma of classification. Clin Dermatol 2005; 23:
311-4.
29 Chopra S, Levell NJ, Cowley G, et al.
Systemic corticosteroids in the phenytoin hypersensitivity
syndrome. Br J Dermatol 1996; 134: 1109-12.
30 Fremia ML. Use of silver sulfadiazine in Stevens-Johnson
syndrome. Ann Pharmacother 1994; 28: 736.
31 Casacci M, Lebas D, Decamps F,
Fourrier F, Delaporte E. Toxic epidermal necrolysis due
to omeprazole. Eur J Dermatol 2006; 16(6): 699-700.
32 Brown T, Apple J, Kasteler J, et al.
Hypersensitive reaction in a child due to lamotrigine. Pediatr
Dermatol 1999; 16: 46-9.
33 Nori S, Nebesio C, Brashear R, et al.
Moxifloxacin – Associated drug hypersensitivity syndrome with toxic
epidermal necrolysis and fulminant hepatic failure. Arch Dermatol
2004; 140: 1537-8.
34 Redondo P, de Felipe I, de la Pena A,
et al. Drug induced hypersensitivity syndrome and toxic
epidermal necrolysis. Treatment with N-acetylcysteine. Br J
Dermatol 1997; 136(4): 645-6.
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