Pharmacology and therapeutics

Severe adverse cutaneous drug eruptions: epidemiological

and clinical features
Inès Zaraa, MD, Meriem Jones, MD, Sondes Trojjet, MD, Rym Cheikh Rouhou, MD,
Dalenda El Euch, MD, Mourad Mokni, MD, Amel Ben Osman, MD

Dermatology Department, La Rabta Abstract

Hospital, Jabbari, Bab Saadoun 1007, Introduction Adverse cutaneous drug reactions (ACDR) are common, and some can be
Tunis, Tunisia
lethal. The aim of our study was to discuss the epidemiological and clinical features of
severe ACDR.
Correspondence
Inès Zaraa, MD Materials and methods We retrospectively analyzed 100 cases of ACDR from 1981 to
Dermatology Department 2007, collected in the Department of Dermatology of the La Rabta Hospital in Tunis, which
La Rabta Hospital is located in the north of Tunisia. Severity was defined on three criteria: hospitalization;
Jabbari
visceral involvement; and severity markers.
Bab Saadoun
Results Characteristics of the 54 included cases were: women (70%); mean age:
Tunis
1007 44.8 years; responsible drugs: anticonvulsants (28%), antibiotics (28%), and nonsteroidal
Tunisia anti-inflammatory drugs (15%). The most common dermatoses were maculopapular rash
E-mail: inesrania@myway.com (50%). We observed fever (76%), lymphadenopathy (31.5%), eosinophilia (35%), and
visceral involvement (50%). Twelve patients died directly related to the ACDR.
Conclusion This study underlines the polymorphous clinical presentation of ACDR
and the importance of researching some severity markers, which have important practical
implications.

presence of severity markers, such as fever, adenomegaly,

Introduction
Adverse cutaneous drug reactions (ACDR) are a frequent
reason for consultations in dermatology.1,2 These reac-
tions are usually benign and self-limited as long as the
causative drug is stopped. In rare cases, ACDRs can be
severe and even life-threatening.2,3
The most common ACDR is morbilliform exanthema
(ME), but it is also the least specific manifestation. Other
potentially severe forms are more specific, but they are
less frequently encountered.3
The aim of our study is to analyze the epidemiological
and clinical characteristics of severe ACDR.
Materials and methods
In this monocentric study, a retrospective analysis of all hospital
records of ACDRs of the Department of Dermatology of La
Rabta Hospital, located in the north of Tunisia (Tunis), during
the years 1981–2007 was conducted. Only the severe forms of
ACDR were included.
The severity criteria used were based on the presence of at
least two criteria in addition to the necessity of hospitalization: a
visceral involvement (kidney, liver, lung, or heart); and the
involvement of more than 60% of body surface, or eosinophilia.1
We recorded the age and sex of the patient, the offending
drug, the time interval between the drug intake and the
eruption, the duration of the eruption, the mucocutaneous signs,
and the results of the paraclinical investigations and
pharmacovigilance investigation.
Based on morphology, distribution of the lesions, and
biological exam of the ACDR, we distinguished: ME; acute
generalized exanthematous pustulosis (AGEP); toxic epidermal
necrolysis (TEN) and Stevens–Johnson syndrome (SJS);
erythroderma (ED); and drug hypersensitivity syndrome (DHS).
Results
During the 27 years of the study, 100 patients were admitted
due to ACDR. Fifty-four of them had a severe form. The
mean age was 44.8 years, ranging from 10 to 81 years. The
male to female ratio was 0.4. Drug exposure duration before
adverse reaction ranged from 3 to 60 days, with an average
of 25 days. Winter preponderance was noted (40%).
The most common presentation was ME (50%). The
various presentations encountered are summarized in
Table 1.
877

ª 2011 The International Society of Dermatology International Journal of Dermatology 2011, 50, 877–880
878 Pharmacology and therapeutics Severe adverse cutaneous drug eruptions Zaraa et al.

Table 1 Clinical subtype of ACDR

Severity Visceral
Hospitalized markers involvement
Clinical subtype cases (cases) (cases)

Morbilliform exanthema (ME) 45 27 7

Acute generalized 12 9 5
exanthematous pustulosis
(AGEP)
Drug hypersensitivity syndrome 7 7 7
(DHS) 9 3 3
Toxic epidermal necrolysis 12 3 2
(TEN)
Erythroderma (ED) 3 1 1
Erythème pigmenté fixe (EPF) 2 1 1
Stevens–Johnson syndrome 2 1 1
(SJS)
Othersa 8 2 0 Figure 2 Face edema in a drug hypersensitivity syndrome
Total 100 54 27 (DHS)

a after an ME. Phenobarbital was the most commonly

Photosensitivity, quincke edema, acute urticaria, vasculitis.
involved drug (six cases). In all other instances, the evolu-
tion was benign.
The anticonvulsants (15 cases: 28%), antibiotics (15
cases: 28%), and nonsteroidal anti-inflammatory drugs
(NSAID; eight cases: 15%) were the main causative drugs.
Other drugs were implicated in the remaining 16 patients,
including: allopurinol (three cases); paracetamol (three
cases); terbinafine (two cases); salazopyrine (two cases);
and chloroquine, captopril, glibenclamide, diltiazem,
iodine contrast product, and acebutolol in one case,
respectively. After pharmacovigilance investigation, the
offending drug was recognized in only 25% of the cases.

Figure 1 Numerous pustules of the trunk in an acute gener-
alized exanthematous pustulosis (AGEP)
Our study included four children (7.4%): three boys
and one girl aged, respectively, 10, 10, 16, and 12 years.
Two of them had toxic TEN and SJS.
Severity signs, such as fever, hypereosinophilia, and
lymphadenopathy, were present, respectively, in 41, 19,
and 17 patients. Visceral involvement was associated in
27 cases. These patients had a mean age of 48 years, with
a male to female ratio of 0.5. The liver was concerned in
23 cases, the kidneys and lungs in three cases each, and
the heart in two cases. Patients died of systemic complica-
tions in 12 cases. The fatal course was mostly observed in
more specific ACDR, such as TEN in five cases, AGEP in
three cases (Fig. 1) and DHS in one case (Fig. 2). In two
cases, death followed an ED and, in another, it occurred
Discussion
Adverse drug reactions may affect any organ, and the
skin is a commonly involved organ. ACDR are usually
benign. Severe forms are rare, with an estimated propor-
tion of 2%.2,4 The course can be fatal in 0.2–29.3% of
cases requiring hospitalization when a severe evolution is
predicted.2
ACDR prevalence is different from one study to
another. It is estimated at 0.33–3% in admitted
patients,2–6 0.14% in non-hospitalized patients, and
0.25% in general.7 The prevalence of ACDR in a French
hospital setting is estimated at 0.75/1000 (10 out of
13,294 hospitalizations), and the incidence of ACDR in
France is estimated at 0.4–1.2 per 1.2–6 million habitants
per year.3 In our study, ACDR represented 1.5% of con-
sultations in dermatology; 3.53% of them required hospi-
talization, and 1.9% were considered as severe.
The results obtained in our study are comparable to
what is reported in the literature: female preponder-
ance,2,7 lesional polymorphism,1 predominance of ME,

International Journal of Dermatology 2011, 50, 877–880 ª 2011 The International Society of Dermatology
Zaraa et al. Severe adverse cutaneous drug eruptions
and the possibility of association of these non-specific
cutaneous eruptions with fever, mucous involvement,
and/or hypereosinophilia.1
As previously reported, symptoms appear usually
within three weeks following the drug intake.
In our study, the increase in ACDR observed in winter
is probably caused by the higher frequency of infections
and therefore of drug intake. Besides, infections are con-
sidered as cofactors in the occurrence of ACDR. Recently,
authors suggested a possible causality link between
HHV6A and HHV7 infection and DHS.8
The most frequent ACDR encountered in the literature
are ME (30–51%,1–19 often induced by antibiotics, repre-
senting more than 3% of the cases.16,17 Despite their high
frequency, these non-specific ACDR remain unclear. Path-
ological findings are equally non-specific, revealing super-
ficial perivascular and dermo-epidermal junction
lymphocytic infiltrate. The only helpful finding is isolated
necrotic keratinocytes in the epidermis. This type of
ACDR is usually mild, but certain ME may evolve into
more severe presentations such as SJS and TEN. Factors
predicting this evolution are fever, mucous membrane
involvement, and hypereosinophilia. This suggests that
ACDR are a spectrum of the same affection ranging from
non-specific and mild ME to the often fatal TEN, with
factors inducing shifting from one to another.9,19
Some predisposing factors were identified in previous
studies. They are mainly non-hereditary, such as age of
patient (over 60 years), female gender, obesity, drug dos-
age, associated drug intake, and associated morbidity,
including immune dysregulation (systemic lupus erythe-
matosus, dysthyroidism, and antiphospholipid antibody
syndrome), and concomitant viral infections.2,8,16
More often, ACDR are described as morbilliform or
maculopapular. Some rashes can be the prelude to much
more severe outcomes, and serious systemic events have
been reported. Specific and severe presentations, such as
TEN, SJS, AGEP, and DHS are associated with high mor-
bidity and mortality rates (up to 10%).2,5,10 TEN and SJS
are the most specific and least frequent forms of ACDR,
with the highest mortality rates reaching 30%.10,15 AGEP
is a severe cutaneous adverse reaction, but after the
suspected drug is withdrawn, the skin heals rapidly, and
mortality is low.15
Although clinical presentation of ACDR does not seem
related to age,14,16,17 a higher frequency has been reported
at extreme ages. This is probably caused by a dysfunction
in the immune system or an insufficiency of drug metabo-
lism. In our study, the mean age was 44.8 years, with a
maximum in the fourth and fifth decade. None of our
patients had a history of drug reaction, a finding not sup-
ported by what has been reported in the literature (31%
vs. 9.3%). Because of the limited number of epidemiologi-
ª 2011 The International Society of Dermatology
Pharmacology and therapeutics 879
cal studies, the frequency of ACDR in children is not
known, but it seems inferior to that of adults.9 In our
study, four children had a severe cutaneous drug reaction.
The pattern of drugs causing ACDR is different accord-
ing to country because of differences in prescription hab-
its.5,19 Drugs most frequently involved are antibiotic
agents, anticonvulsants, and NSAIDs.1–19 New forms of
drug eruptions will probably develop because new drugs
are continuously becoming available.9,18,19
ACDR can be life threatening,10 requiring hospitaliza-
tion,11 sometimes even intensive care units.2,10 Evolution
was fatal in 12 of our cases. The anticonvulsants were
the most common offending drugs (phenobarbital).
Only a few studies have analyzed severity markers of
ACDR: Djien’s study1 suggests a possible association
between the severity of the eruption and the occurrence
of fever (60%), adenomegaly (30%), eosiniphilia (44%),
or visceral involvement (22%).
This study underlines the polymorphous clinical presen-
tation of skin reactions to drugs and proposes that for
polymorphous drug reactions, research into severity clini-
cal markers that have important practical implications is
needed. ACDR represent a real public health problem,
which all dermatologists may be confronted with. ACDR
management includes the description of skin manifesta-
tions, evaluation of severity signs, and appropriate treat-
ment. A precise counsel has to be provided to the patient
concerning his future drug intake. ACDR can be avoided
in 15% of cases.6 A careful and adequate prescription of
medication with a reduction in the number of drugs may
help reduce the frequency of drug reactions, especially in
advanced-aged patients.3
However, it is essential that any rash be carefully
monitored for possible, but rare, serious systemic events
ensuing.
Conclusions
Our study showed the importance of a thorough clinical
and biological examination in the management of patients
with specific forms of drug eruption, in search of severity
makers enabling the detection of visceral involvement that
require specific treatment. Besides, any prescription has to
be justified because it could be responsible for a severe
life-threatening ACDR.
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