acute generalized exanthematous pustulosis induced by ingestion of bamifylline

634

© 2002 European Academy of Dermatology and Venereology

CAS E REPO R T

JEADV

(2002)

16

, 634–637

Blackwell Science, Ltd

Acute generalized exanthematous pustulosis induced by ingestion of bamifylline

C

Galvão,†

RFJ

Criado,†

PR

Criado,‡*

NYS

Valente,‡ JF

de Mello,†

MFM

Fernandes†

†

Allergy and Immunology Unit,

‡

Dermatology Unit, Hospital do Servidor Público Estadual de São Paulo, Brazil.

*

Corresponding author, Rua Xingú,

245/182, Bairro Valparaíso, Santo André, São Paulo, 09060-050, Brazil, tel./fax +55 11 50888293; E-mail: [email protected]

ABSTRACT

We report a case of acute generalized exanthematous pustulosis (AGEP) in a 64-year-old woman, associatedwith the use of bamifylline. To the best of our knowledge there have been no previous reports of AGEPinduced by the ingestion of bamifylline in the medical literature. We, therefore, add this drug to the list ofcauses for AGEP.

Key words:

acute generalized exanthematous pustulosis, bamifylline, neutrophilic drug eruptions

Received: 11 December 2001, accepted 15 February 2002

Introduction

Acute generalized exanthematous pustulosis (AGEP) is charac-

terized by a widespread sterile pustular rash occurring suddenly,

accompanied by fever and neutrophilia on scarlatiniform

erythema.

1,2

AGEP is a potentially severe disease caused by drug

intake in about 80% of cases,

3

particularly by antibiotics, and

also by mercurial antiseptics,

1

topical bufexamac,

1

ingestion

of lacquer chicken,

2

ultraviolet light exposure and viral infections.

4

The patch test is an elegant alternative to prove the causative

role of a suspect drug,

5

but it is performed rarely in AGEP and

most of it reproduces eczematiform lesions.

6

Oral rechallenge is

not ethical because it may provoke a generalized eruption, even

at a low dose.

5

We describe a case of AGEP provoked by bamifylline, an

bronchodilator derivative of theophylline, formerly named 8-

benzyl-7-[2-(

N

-ethyl-

N

-2 hydroxyethyamino) ethyl] theophyl-

line, with longer mean elimination half-life (20.5 h) and high

estimated potency.

7

Case report

A 64-year-old white woman was admitted with a febrile erup-

tion (38.5

°

C) of acute onset. Three days before the admission,

the patient initiated treatment with bamifylline for asthma con-

trol and noticed that 12 h after taking one tablet of the medication,

a cutaneous rash suddenly began. She did not have a past history

of personal or family psoriasis or contact dermatitis. Clinical

examination showed a generalized, symmetrical erythema,

with numerous discrete non-follicular pustules on intertriginous

areas, the extensor surfaces of arms (fig. 1), forearms, trunk

and proximal thighs (fig. 2). Other medications included oral

prednisone, which had been taken routinely for many years,

at a moderated dose (20 mg/d), to control severe asthma, dia-

gnosed 8 years ago.

Six months before she noticed a similar febrile cutaneous

eruption after taking the same drug, but she did not call on a

physician.

fig. 1 Small non-follicular pustules on erythematous and oedematous skin

on the arm.

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On hospital admission laboratory evaluation revealed a total

white blood cell count of 10.2

×

10

9

/L with 90% neutrophils,

raised erythrocyte sedimentation rate (40 mm during the first

hour), and normal serum calcium, blood sugar, renal and liver

function tests.

Biopsy of the skin demonstrated an intracorneal pustule in

epidermis and a mixed interstitial and perivascular inflamma-

tory cell infiltrate within upper dermis (fig. 3). Tissue samples

for Gram’s stain and periodic acid-Schiff were negative for bac-

terial and fungal elements, respectively, and smears obtained for

bacterial and fungal cultures were negative.

Bamifylline was discontinued. Treatment with systemic

hydrocortisone acetate 200 mg, every 6 hours, intravenously

and oral hydroxyzine 75 mg/d led to cutaneous lesions resolu-

tion in 3 days.

The patch test was carried out 1 month later with Brazilian

standard series and with pure bamifylline and diluted only by

10% in white petrolatum. The tests were performed in 10 good

healthy volunteers’ controls too. The patch test with Finn Chambers

on Scampor® was negative at 48 and 96 h in the patient and con-

trols. At this time the patient was receiving prednisone 20 mg/d

to control her severe glucocorticoid-dependent asthma.

Despite our written and oral recommendations, the patient

ingested bamifylline 6 months later and developed another

similar generalized pustular eruption.

Discussion

This case fulfilled the clinical and histological diagnostic criteria

of AGEP established by Roujeau

et al

.

3

This is the first reported

case with bamifylline. Other authors reported cutaneous

adverse reactions to this drug, such as ‘toxic dermatitis (erythro-

derma)’,

8

‘exanthem’

9,10

and ‘erythema multiforme-like’.

9

Drug ingestion has been involved in the development of an

acute eruption of disseminated sterile pustules.

11

Among 104

cases of pustular psoriasis described by Baker and Ryan in

1968,

12

they reported a subgroup of five patients who had a very

acute pustular eruption for which a drug had been given and

who had no history of psoriasis. This subgroup was named

exanthematic pustular psoriasis. The authors suspected drugs

and/or infections as a trigger for this reaction. Later other sim-

ilar cases were reported under different denominations such as

toxic pustuloderma

13

and pustular drug rash.

14

Beylot

et al

.

15

introduced the name pustuloses exanthématique aiguës

généralisés in 1980 and its translation acute generalized exan-

thematous pustulosis is nowadays used to repute the pustular

eruptions with the clinical aspects discussed below.

AGEP mostly beginning in the intertriginous areas or on the

face as a diffuse, often oedematous erythema develops very

acutely, and on this erythema soon dozens to hundreds of small

(pinhead sized, < 5 mm) non-follicular sterile pustules arise

mainly in the folds.

16

In our patient the eruption developed

12 hours after bamifylline ingestion, very acutely, beginning in

intertriginous areas, especially on inguinal and axillar folds,

and with pinhead non-follicular pustules. Skin symptoms

are almost always accompanied by fever above 38

°

C and

fig. 2 Erythema multiform aspects often associated with pustules on the

proximal thigh.

fig. 3 Skin biopsy showed intracorneal pustule with neutrophils and spon-

giosis. In the dermis, a mixed interstitial and perivascular infiltrate of neu-

trophils and lymphocytes was present (haematoxylin and eosin, original

magnification, × 63).


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et al.


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leucocytosis mostly due to neutrophil counts above 7

×

10

9

/L.

16

The fever (38.5

°

C) and the blood neutrophil counts (9180/mm

3

)

combined with hundreds of small non-follicular sterile pustules

led to the diagnosis of AGEP. Lymphadenopathy has been

reported in some cases, slight reduction of the creatinine clear-

ance (< 60 mL/min in

≈

30% of the cases) and a mild elevation

of aminotransferases.

16

The histopathology of AGEP shows spongiform, subcorneal

and/or intraepidermal pustules, an often-marked oedema of

the papillary dermis and perivascular infiltrates of neutrophils

and exocytosis of some eosinophils.

3,16

In our case there were

intracorneal pustules and a mixed interstitial and perivascu-

lar inflammatory cell infiltrate within the upper dermis.

Acanthosis and papillomatosis resembling psoriasis are usually

absent.

1

Some cell necroses of keratinocytes and/or vasculitis

may be present.

3,16

Patch test is a valuable tool, but its sensitivity is about 50%,

and negative tests do not allow a final conclusion.

5

The patient

was receiving prednisone, and this drug could have been inter-

fered in patch tests results; however, Rietschel and Fowler

17

noticed that patch tests could be performed even in patients

using 30 mg/d of prednisone without influencing the results.

False-negative drug patch test results can be attributable to

various causes. The drug being tested may be unable to pene-

trate into epidermis, or the culprit source of the cutaneous

adverse drug reaction was not the native drug itself but one of

its metabolites.

18

The most convincing proof that the bamifylline was probably

the causative agent is substantiated in the observation that after

the first pustular rash, she ingested bamifylline again 6 months

later by accident and in 2 days a new pustular eruption occurred.

Recently, Britschgi

et al

.

19

presented clinical and immuno-

logical data on four patients with AGEP, and demonstrated an

expression of the potent neutrophil-attracting chemokine

interleukin-8 in keratinocytes and infiltrating mononuclear

cells. The authors conclude that AGEP appears to be a reaction

where a cell-bound drug presentation elicits a drug-specific

CD4 and CD8 immune response, which results in an interleukin-

8 elevated expression.

The main differential diagnosis is acute pustular psoriasis

von Zumbusch type.

6

A wide spectrum of cutaneous diseases or

conditions can cause pustular eruptions:

16

all follicular erup-

tions, such as bacterial folliculitis, furunculosis, acne and acnei-

form reactions, dermatophyte infections, Sweet’s syndrome,

localized pustular contact dermatitis, impetiginized eczema,

subcorneal pustular dermatosis (Sneddon–Wilkinson dis-

ease), pustular vasculitis, Behçet’s disease or staphylococcal

scalded skin syndrome and others. Drug hypersensitivity syn-

drome, also referred to as DRESS (

D

rug

R

ash with

E

osinophilia

and

S

ystemic

S

ymptoms) may also show generalized papulo-

pustules being usually less pronounced than in AGEP.

16

Many authors have discussed the differentiation between

AGEP and pustular psoriasis of the von Zumbusch type. Beylot

et al

.

15

discuss the rare but possible occurrence of such a pustu-

losis in patients with a genetic psoriatic predisposition. Sidoroff

et al

.

16

suggests a list of differences that seems to justify the dis-

tinction between AGEP and pustular psoriasis. In AGEP: (i) his-

tory of psoriasis is possible; (ii) pustules predominate in the

folds; (iii) the duration of the pustules and fever is shorter;

(iv) there is a history of drug reaction and recent drug use;

(v) arthritis is rare; and (vi) no papillomatosis and acanthosis

in histopathology. In pustular psoriasis: (i) most patients have

a history of psoriasis; (ii) the distribution of the pustules is more

generalized; (iii) the duration of pustules and fever is longer;

(iv) a history of drug reaction and recent drug use are uncom-

mon; (v) arthritis occurs in approximately 30% of patients; and

(vi) the histopathology shows papillomatosis and acanthosis.

Various drugs, such as lithium and beta-blockers, have also

been reported as being able to induce the development of pus-

tular psoriasis in patients previously known to have psoriasis.

11

Some reports suggest that beta-blockers could also induce a

predominantly pustular eruption in patients with no history of

psoriasis.

20

At this moment there are no precise descriptions

of whether this latter type of eruption is a variant of pustular

psoriasis or if it is true AGEP.

The most important aspect of management of AGEP is the

immediate withdrawal of the suspect drug. It must be empha-

sized that AGEP is defined by a clinical syndrome that is most

often drug induced and we are adding a new drug (bamifylline)

to the list of causes of AGEP.

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acute generalized exanthematous pustulosis induced by ingestion of bamifylline

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