The Journal of Dermatology

Vol. 31: 10091013, 2004

Drug-Induced Hypersensitivity Syndrome Due to

Anticonvulsants in a Two-Year-Old Boy
Paulo Ricardo Criado, Roberta F. J. Criado*, Cidia Vasconcellos**,
Jose Roberto P. Pegas and Patrcia Calil Cera
Abstract
Drug-induced hypersensitivity syndrome (DIHS) usually refers to severe cutaneous drug
eruption associated with systemic involvement and potentially fatal outcome. We report a
2-year-old Caucasian boy who developed DIHS due to phenytoin and phenobarbital and
who showed extensive internal organ involvement. We are alerting that failure to recognize this drug eruption and discontinue the culprit drug may result in increased severity,
greater extent of internal organ involvement, and fatal outcome. The recent research
about the influence of human herpesvirus 6 co-infection on the pathogenesis of DIHS is
also discussed by the authors in this paper.
Key words: severe cutaneous drug eruptions; drug-induced hypersensitivity syndrome
(DIHS); phenytoin; antiepileptic hypersensitivity syndrome; human herpesvirus 6

Introduction
A variety of cutaneous drug reactions may
be induced by aromatic anticonvulsants, including, as exanthematous eruptions,
Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyells syndrome), as
well as the drug-induced hypersensitivity
syndrome (DIHS) (1). The expression hypersensitivity syndrome refers to a specific
severe idiosyncratic reaction that includes
skin rash and fever, and often accompanies
hepatitis, arthralgias, lymphadenopathy
and/or hematological abnormalities (2).
Accurate and timely diagnosis in the pediatric patient may be particularly challenging
because two prominent signs of this syndrome, cutaneous eruption and fever, are
Received January 6, 2004; accepted for publication
July 26, 2004.
Dermatology Unit, Complexo Hospitalar Padre
Bento de Guarulhos, *Allergy Unit Hospital do Servidor Pblico Estadual de So Paulo, **LIM 53 HC-Faculdade de Medicina da Universidade de So Paulo
(FMUSP), Brazil.
Reprint requests to: Paulo Ricardo Criado, M.D.,
Rua Xingu, 245/182 - B,Valparaso, Santo Andr
Brazil, Zip Code 09060-050, Brazil.

frequent and non-specific signs of systemic

diseases in children (3). Infection, particularly viral illness, is frequently the initial diagnosis and may delay detection of the culprit drug (3).
All types of cutaneous eruptions are reported during phenytoin therapy, and most
of them are morbilliform exanthemas that
fade even if the drug is continued (2). Unfortunately, the eruption often presents initially as a morbilliform exanthema indistinguishable from less serious drug reactions
or common childhood infectious diseases
(2, 4). Several groups have reported an association between human herpesvirus 6
(HHV6) reactivation and drug-induced hypersensitivity syndrome (514). We report a
case of DIHS in a child and summarise the
recent findings about the association of
HHV6 with DIHS.
Case Report
A 2-year-old Caucasian boy presented with a
seven-day history of fever, malaise, and exanthema 30 days after the introduction of phenytoin
therapy for the treatment of seizures. The boy
was admitted to a pediatric infirmary, and the
drug was switched to phenobarbital with clinical

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Criado et al

Fig. 1. Diffuse infiltrated exanthematous maculo-papular eruption with lamellar desquamation. Observe the facial and hand edema.
progressive deterioration. At this time, the child
was referred to our dermatological unit for evaluation. There was no medical history of smallpox, measles, or scarlet fever. The mother mentioned a fever episode in the first year of his life
that appeared to be exanthema subitum. This
information was gotten from the parents and we
could not confirm it in his medical records.
Thus, the diagnosis of exanthema subitum was
uncertain. General physical examination revealed fever (38C), tachypneia, ictericia +++/
++++, generalized lymphadenopathy, and hepatoesplenomegaly.
The dermatological exam showed a maculopapular exanthema (Fig. 1) with dusky erythema and edema of the face, especially in the periorbital area. The cutaneous eruption was distributed on the trunk and on the proximal aspects
of the arms and thighs. In some areas, the erythema was followed by exfoliative scaling.
Abnormal laboratory results included leuco-

cytosis, 20,600 cells/mm3 (normal 4,00010,000

cells/mm3); anemia 8.2 g/dl (normal 1114
g/dl); elevated liver enzymes: aspartate transaminases (AST), 2,088 U/L (normal 1759 U/L),
alanine aminotransferase (ALT), 1,251 U/L
(normal 2043 U/L). Bilirrubin levels were 6
mg/dl (total bilirrubin), direct bilirrubin 5
mg/dl, and indirect bilirrubin 1 mg/dl. Protrombin activity time was 29.8% (normal 70
100%). He had hypoalbuminemia at 2.9 g/dl
(normal 3.55.5 g/dl). The radiological thorax
studies show diffuse interstitial infiltrates in both
lungs. Titers were negative for hepatitis A, B and
C, Epstein-Barr virus, human immunodeficiency
virus, toxoplasmosis, rubella, and cytomegalovirus. The human herpesvirus 6 serology and HHV-6 DNA by real time PCR (polymerase chain reaction) detection were not available in our case. The auto-antibodies panel, antiSSA, anti-SSB, ANA, and rheumatoid factor were
negative, and the serum complement was normal. A skin biopsy was not performed because of
low prothrombin levels.
The seizure medications were stopped and
changed to valproic acid. The patient was treated in the pediatric intensive care unit with
methylprednisolone IV (3 mg/kg/dose) and
subsequently prednisone per os (1 mg/kg/day)
was introduced for 15 further days. At the 5th
day of corticosteroid introduction, the boy
showed some improvement of liver function,
consciousness level, and progressive regression
of the cutaneous eruption, with subsidence of
exfoliative desquamation. The patient was discharged on the 12th day after admission.

Discussion
The overall population risk of DIHS due
to the use of aromatic antiepileptics (phenytoin, carbamazepine and phenobarbital) is
estimated to be between 1:1,000 and
1:10,000 (2, 3). Other drugs, especially
sulphonamide, alopurinol, gold salts, dapsone, sorbinil, minocycline, terbinafine, zidovudine, nevirapine and zalcitabine, can
also be associated with this syndrome (2, 3,
15). Drug-induced hypersensitivity syndrome may be difficult to distinguish from
other conditions such as serum sickness,

Drug-Induced Hypersensitivity Syndrome

drug-induced vasculitis, and infectious diseases (2). General physicians frequently use
the generic term rash to describe exanthemas of many etiologies (4). Despite the difficulty of the etiologic classification of febrile
exanthema cases, early recognition of severe
drug eruptions such as DIHS is critical in reducing multiorgan involvement and fatal
outcome.
DIHS is distinguished from other adverse
drug reactions from several aspects: the limited number of causative drugs, late onset,
clinical similarity to many infectious diseases
and show prolonged resolution of symptoms
and signs (2, 13). In 1998, Tohyama et al. (5)
and Suzuki et al. (6) characterized a new
link between viral infection and drug adverse reaction, namely between DIHS and
HHV6. These authors suggested that HHV6
infection could play a role in the development of DIHS in susceptible patients (9,
13). It seems that the activation of monocytes and CD4+ T lymphocytes induced by
the adverse drug reaction results in the reactivation of a latent HHV6 infection (13).
The HHV6 infection modulates the production of a number of cytokines (13), including interleukin (IL) 10, IL12 , IL15, and
pro-inflammatory cytokines including interferon (IFN), tumor necrosis factor-
(TNF) and IL1, which may in turn induce
dysfunction of the immune system and an
inflammatory reaction (13).
Hashimoto et al. (13) analysed more than
20 patients with DIHS by using a quantitative, real-time polymerase chain reaction
(PCR) assay of serial serum and blood patient samples, as well as making measures of
the anti-HHV6 IgG titers. He proposed a
basic pattern of the relationship between
clinical disease and HHV6 reactivation in
DIHS: (i) exposure to causative drug with 2
to 6 weeks of drug sensitisation, (ii) first
peak of symptoms and signs of DIHS with
fever, rash, liver dysfunction and (iii) second peak of clinical symptoms and signs
representing the typical manifestations of
slow resolution and simultaneous to antiHHV6 antibody titers increasing in the third

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and fourth week. This second peak is preceded by detection of HHV6 DNA by PCR
(13).
Kano et al. (14) studied 10 patients with
DIHS due to anticonvulsants, and two
groups of patients receiving anticonvulsants
as controls. The detection of HHV6 DNA by
real-time PCR in peripheral blood mononuclear cells (PBMC) preceded the dramatic
increase (more than 4-fold) in anti-HHV6
IgG titers, and HHV6 DNA was positive by
PCR in sequential blood samples. These increases in HHV-6 IgG titers and HHV-6 DNA
positivity were exclusively detected in patients with DIHS due to anticonvulsants associated decreased serum IgG levels and decreased B-cell counts, but not in those patients receiving the same drugs but without
DIHS (controls) (14). These results of Kano
et al. (14) indicated that selective reactivation of HHV-6 might be specific to DIHS
due to anticonvulsants. HHV-6 reactivation
associated with the development of DHIS
due to anticonvulsants could occur as a result of transient immune dysfunction, such
as decreased IgG production, probably induced by continuous anticonvulsant therapy
(14).
Cutaneous findings are present in almost
all children with DIHS. (3). They begin on
the face, upper trunk, and proximal extremities as dusky red papules and macules that
coalescence into larger patches or generalized erythroderma, finally producing a
brawny desquamation of the skin (3). Like
adults with DIHS, the pediatric patients
show a prominent facial edema, particularly
in the periorbital area, similar to the pattern
observed in our patient (3). The liver is the
most frequently (61%) (3) involved organ,
producing coagulopathy, hepatitis, hepatic
failure, hepatomegaly and hypoalbuminemia, all systemic manifestations observed in
our patient. Other damaged organs or systems include: blood (48% with anemia,
eosinophilia, leucopenia, leucocytosis, and
thrombocytopenia), kidneys (15% with creatinine elevation, hematuria, nephritis, and
proteinuria), lungs (14% with atalectasis,

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consolidation, effusions, dyspnea, hypoxemia, pulmonary edema, and pneumonitis)

and others (20% with pancreatitis, nausea,
emesis, diarrhoea, hyper/hypothyroidism,
myocardititis, splenomegaly, seizures, altered mental status, and syndrome of inappropriate anti-diuretic hormone secretion)
(3). There was one case of child fatality (3).
The following criteria for DIHS diagnosis
have been proposed (16): (i) cutaneous
drug eruption; (ii) hematological abnormalities: eosinophilia >1.5 109/L or presence of atypical lymphocytes; (iii) systemic
involvement: adenopathies (>2 cm in diameter) or hepatitis (liver transaminases values
2 normal range) or interstitial nephritis or
interstitial pneumonitis or carditis. A patient is said to have a DIHS if three of those
criteria are present (16). Our patient developed at least four of these criteria: cutaneous drug eruption in a typical pattern,
generalized lymphadenopathy, interstitial
diffuse infiltrates in the lungs, and severe
hepatitis. The differential diagnosis of DIHS
includes other drug reactions (drug-induced pseudolymphoma, Stevens-Johnson
syndrome, toxic epidermal necrolysis and
acute generalized exanthematic pustulosis),
some acute viral infections (Epstein-Barr
virus, hepatitis viruses, influenza virus, cytomegalovirus, and the human immunodeficiency virus), lymphoma, pseudolymphoma, idiopathic hypereosinophilic syndrome, and angio-immunoblastic lymphadenopathy (16).
Our case is a typical example indicating
that physicians must be aware of any cutaneous reaction associated with aromatic anticonvulsant agents more than two weeks
after therapy is initiated, because they can
be especially severe and constitute a DIHS
(2). Cross reactivity among phenytoin
(PHT), carbamazepine (CBZ) and phenobarbital (PB) is as high as 7080% (17); this
may explain why some symptoms continue
to progress or recur after switching to another aromatic anticonvulsant drug (18).
This is probably what occurred with our patient in the pediatric infirmary. A benzodi-

azepine should be chosen for seizure control (18); valproic acid is also an alternative,
but because of its hepatic metabolism, it
should not be used during the acute or convalescent phase of DIHS (18). Unfortunaly,
there are few data on DIHS relating specifically to children (18), but we are adding a
new case. To the best of our knowledge our
patient is one of the youngest children reported in the medical literature with DIHS.
Because no gold standard for the diagnosis of DHIS due to anticonvulsants exists, selective reactivation of HHV-6 associated with
decreased serum IgG levels and decreased
B-cell counts can be reliable markers for an
increased risk of developing DIHS due to
anticonvulsants in these patients (14).
The prompt recognition of DIHS and immediate withdrawal of the suspected drugs
are critical in the management of these patients to prevent or minimize more serious
sequelae involving internal organs (3).
Use of systemic corticosteroids (prednisone >0.5 mg/kg/day or equivalent) has
been widely advocated for the treatment of
DIHS (2). The mechanisms involved, the
data of Kano et al. (14) point to a therapeutic use of intravenous immunoglobulin
(IVIG) containing high HHV-6 IgG titers for
the treatment of severe DIHS due to anticonvulsants (14).
Hashimoto et al. (13) suggest investigation of the usefulness of the combination of
systemic corticosteroids and high-dose IVIG
used for the treatment of Stevens-Johnson
syndrome and toxic epidermal necrolysis,
especially in patients with severe DIHS (19).
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