CASE REPORT

Acute generalized exanthematous pustulosis associatedwith pseudoephedrine

M . A . P A D I A L , J . A L V A R E Z - F E R R E I R A , * B . T A P I A , R . B L A N C O , C . M A N A S ,

M . B L A N C A † A N D T . B E L L O N

Departments of Allergy and *Pathology, Hospital Universitario �La Paz�, P �Castellana 261, 28046 Madrid, Spain

†Department of Allergy, Hospital Carlos Haya, Malaga, Spain

Accepted for publication 25 July 2003

Summary Acute generalized exanthematous pustulosis (AGEP) is an uncommon skin disorder most often

caused by drugs. Few adverse reactions to sympathomimetic drugs have been reported, despite their

extensive use. Although the aetiology of AGEP remains uncertain, recent data have reported

involvement of drug-specific T cells and interleukin (IL)-8 production. We characterized an adverse

reaction to pseudoephedrine both clinically and immunologically. Histological analysis of skin

biopsies confirmed the clinical entity as AGEP, while epicutaneous tests confirmed the specificity of

the reaction to the drug. Moreover, immunohistochemical studies showed a mononuclear infiltrate

consisting of activated memory T cells in addition to polymorphonuclear cells. Reverse

transcription-polymerase chain reaction revealed an increased expression of IL-8 in AGEP-

affected skin.

Key words: acute generalized exanthematous pustulosis, interleukin-8, lymphocytes,

pseudoephedrine, pustulosis

Acute generalized exanthematous pustulosis (AGEP) is

an uncommon skin disease involving sterile pustules

on an erythematous background. It is mainly caused

by drugs, particularly antibacterial drugs such as

aminopenicillins and macrolides, by acute infection

with enteroviruses, or by mercury.1 Positive skin patch

tests and lymphocyte transformation tests suggest

involvement of T cells in AGEP.2 Moreover, a high

expression of the potent neutrophil-attracting chemo-

kine interleukin (IL)-8 has been detected in keratino-

cytes and infiltrating mononuclear cells in positive

patch-test samples from patients with AGEP.2

Pseudoephedrine is a sympathomimetic drug widely

found in pharmacological preparations for the common

cold. Adverse reactions to sympathomimetic drugs are

rare despite extensive use. Nonpigmented fixed exan-

thema,3,4 and generalized scarlatiniform5 or eczema-

tous eruptions6 have been reported.

We describe a woman who presented with AGEP

after administration of pseudoephedrine. Patch testing

with pseudoephedrine and other sympathomimetic

drugs was performed to identify cross-reactivity. The

immunohistochemical study of the positive patch test

and analysis of cytokine profiles and lymphocyte

proliferation results are reported.

Case report

A 42-year-old woman with no relevant medical history

was referred because of a suspected adverse drug

reaction. Two months previously she had had an upper

airway infection, for which her physician prescribed

Vincigrip (Salvat Laboratory, Barcelona, Spain) con-

taining paracetamol, pseudoephedrine, chlorphenam-

ine and several excipients. Ten hours after the first dose

she developed fever above 38 �C and a pustular

eruption with erythema located on the face, trunk and

proximal extremities. She was admitted by the derma-

tologist to the emergency room where a skin biopsy was

performed and treatment was commenced with oralCorrespondence: Dr Teresa Bellon.

E-mail: tbellon.hulp@salud.madrid.org

British Journal of Dermatology 2004; 150: 139–142.

� 2004 British Association of Dermatologists 139

corticosteroids, with total recovery in 10 days. The

content of the superficial pustules was sterile and the

histopathological findings were spongiform superficial

pustules and papillary oedema with focal necrosis of

keratinocytes (not shown); a diagnosis of AGEP related

to drugs was made. As the patient had taken both

paracetamol and chlorphenamine since the reaction,

pseudoephedrine was suspected to be the culprit drug.

Materials and methods

Patch testing

Patch tests were performed at least 2 months after

recovery with the pharmacological preparation Vinci-

grip (paracetamol, pseudoephedrine, chlorphenamine

and excipients), pseudoephedrine and other sympath-

omimetic drugs (phenylephrine, ephedrine, epineph-

rine and norepinephrine) diluted to 20% and 50% in

petrolatum. The freshly prepared drug ⁄ petrolatum

mixtures were applied on the upper back in the patch

test plaster Leukotest (Beiersdorf, Hamburg, Germany).

Patch test reactions were read at 48 and 96 h and

scored according to the International Contact Derma-

titis Research Group.7

Immunohistochemistry

Punch biopsy specimens were fixed in 10% formalin,

routinely processed, paraffin-embedded and stained

with haematoxylin and eosin for standard histological

analysis. Immunostaining was performed in 5-lm

sections from the positive epicutaneous test reaction

for CD3, CD4, CD8, CD25, CD45RO and CD45RA using

a horseradish peroxidase-based detection technique

and EnVisionTM+ system (Dako Cytomation; Dako,

Glostrup, Denmark).

Reverse transcription-polymerase chain reaction

Sections of 5 lm from paraffin-embedded tissues were

cut with disposable blades, collected on glass slides,

deparaffinized with xylene, washed with ethanol, and

rehydrated in deionized water. The moist tissue was

scraped off the glass slides with a sterile blade. RNA

was extracted in 200 lL TriReagent� according to the

manufacturer’s instructions and reverse transcribed

with random primers and avian myeloblastosis virus

reverse transcriptase. IL-8 mRNA was amplified by

polymerase chain reaction (PCR) using primers 5¢-AAG

GAACCATCTCACTGTGTG-3¢ and 5¢-GGTGGAAAGGT

TTGGAGTATG-3¢. Human cutaneous T cell-attracting

chemokine (CTACK) transcripts were detected with

primers 5¢-CTGTACTCAGCTCTACCGAAAGC-3¢ and

5¢-GTGGATGCAGATGCTGCGTTG-3¢. One hundred

and eighty base pairs of the b2-microglobulin gene

were amplified as a loading control with the primers

5¢-CCAGCAGAGAATGGAAGGTC-3¢ and 5¢-CAGTGGG

GGTGAATTCAGTG-3¢.

Lymphocyte proliferation assays

Peripheral blood mononuclear cells (PBMC) were

isolated from heparinized blood by Ficoll–Hypaque

(Pharmacia, Uppsala, Sweden) density gradient cen-

trifugation. PBMC were seeded at 106 cells mL)1 in

triplicate in round-bottomed 96-well plates at a final

volume of 200 lL. The culture medium was RPMI plus

5% autologous serum and different concentrations of

drugs, ranging from 500 to 1 lg mL)1. The cultures

were incubated for 5 days at 37 �C in 5% CO2 and

1 lCi 3H-thymidine was added to each well 18 h prior

to cell harvesting. The cultures were harvested on to

glassfibre filters and 3H incorporation was estimated by

scintillation counting.

Phytohaemagglutinin and tetanus toxoid were used

as positive controls. The stimulation index (SI) was

calculated as the ratio between the mean values of

counts per minute in cultures with antigen and those

obtained without antigen. An SI > 2 was regarded as a

positive response.

Results

Patch testing with both the commercial preparation

Vincigrip and pseudoephedrine showed an intense

positive result at 48 h, with erythema and papules

that persisted for 96 h. However, the epicutaneous

tests with other sympathomimetic drugs were negative.

Patch tests were also performed on two atopic patients

and two healthy individuals as control subjects, with

negative responses in all cases. Oral challenge with

phenylephrine (7Æ5 mg) and ephedrine (5 mg) were

negative. The patient was also tested with subcuta-

neous epinephrine 1 ⁄ 1000 (0Æ3 mL), with a negative

response.

A punch biopsy specimen (4 mm) was obtained from

the positive epicutaneous test reaction with pseudo-

ephedrine. Histopathology showed subcorneal pustules,

papillary oedema, focal necrosis of keratinocytes and

the presence of subepidermal polymorphonuclear neu-

trophils with a perivascular infiltrate of mononuclear

1 4 0 M . A . P A D I A L et al.

� 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 139–142

and polymorphonuclear cells (Fig. 1A). The mono-

nuclear infiltrate was composed mainly of CD4+ T cells,

although CD8+ lymphocytes were also present in

significant numbers. Furthermore, there was also a

strong positive staining for CD25 and CD45RO

(Fig. 1B), but negative for CD45RA (not shown). These

results indicate that activated memory T cells of the

CD4 and CD8 phenotype were infiltrating AGEP-

affected skin.

It has been suggested that local IL-8 production in

the skin is a key factor in the development of AGEP.2

Therefore, to address the issue of whether IL-8

expression was increased in the skin biopsy taken

from the positive epicutaneous test, we performed

reverse transcription-PCR to amplify IL-8 transcripts.

As shown in Figure 2, IL-8 expression was increased

in the biopsy obtained from the positive epicutaneous

test with pseudoephedrine as well as from the

specimen taken during the acute reaction (lanes 2

Figure 1. Immunohistochemical study of skin biopsy from positive epicutaneous test to pseudoephedrine at 48 h. (A) Haematoxylin and eosin

staining (original magnification · 400). (B) Immunostaining for phenotype characterization of lymphocytic infiltrate with monoclonal antibodies

specific for CD3, CD4, CD8, CD45RO and CD25 (original magnification · 200).

1 2 3 4 5

IL-8

CTACK

ββ2-m

Figure 2. Reverse transcription-polymerase chain reaction (PCR)

analysis of interleukin (IL)-8 mRNA expression in skin biopsy. Total

RNA was purified from 5-lm slices from paraffin-embedded tissue and

reverse transcribed. IL-8 and cutaneous T cell-attracting chemokine

(CTACK) mRNA were PCR amplified from acute generalized exan-

thematous pustulosis (AGEP)-positive epicutaneous test (lane 2),

AGEP acute reaction (lane 3) and two nonrelated clinical entities:

non-immediate urticaria (lane 4) and immediate urticaria (lane 5).

No cDNA was added in lane 1. b2-microglobulin (b2-m) was amplified

as a loading control.

A G E P C A U S E D B Y P S E U D O E P H E D R I N E 1 4 1

� 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 139–142

and 3) in comparison with two samples obtained from

nonrelated clinical entities for which IL-8 mRNA was

not detected (lane 4, non-immediate urticaria; and lane

5, immediate urticaria). In contrast, expression of

CTACK, a chemokine constitutively expressed in kera-

tinocytes, was detected in all cases (lanes 2, 3 and 4).

Lymphocyte proliferation assays were performed in

which PBMC from the patient after resolution of the

disease were cultured in the presence of different doses

of pseudoephedrine and other sympathomimetic drugs.

After 5 days of culture no specific cell proliferation was

detected in response to pseudoephedrine or the different

drug analogues tested (not shown).

Discussion

Pseudoephedrine was the agent responsible for this

severe reaction in our patient, as confirmed by

clinical and patch test data. Histopathological findings

confirmed AGEP as the clinical entity involved.

Although occasionally the aetiology of AGEP appears

to be a viral infection or a hypersensitivity reaction to

mercury, most cases of AGEP (90%) have been

described in association with the intake of drugs,

such as aminopenicillins.8 There is only one previous

report of this unusual reaction due to pseudoephe-

drine, with a positive patch test.9 In our case the

similar histopathological traits found in the biopsy

specimen obtained after oral administration of pseu-

doephedrine and the positive patch test biopsy with

pseudoephedrine validate the reliability of patch

testing in this type of reaction, in agreement with

previous reports.2,10,11

Several studies indicate cross-reactivity between

pseudoephedrine and ephedrine, which have a very

close chemical structure derived from the phenylpro-

panolamine skeleton.12,13 However, in our patient we

were unable to demonstrate any cross-sensitivity to

other sympathomimetic drugs.

Recent studies have involved T cells in the aetio-

pathology of this clinical entity.2 Immunohistochemistry

of the lesions in the positive epicutaneous reaction

confirmed the presence of a perivascular T-cell infiltrate

composed mainly of proliferating activated memory

lymphocytes in addition to the polymorphonuclear

cells. Moreover, we confirmed the increase in the local

production of IL-8 (CXCL-8) in the skin, a chemokine

classically involved in the differentiation and recruit-

ment of neutrophils.

In spite of the presence of a considerable number of

CD25+ T cells in the cutaneous infiltrate, we detected

no positive proliferative response when PBMC from the

patient were cultured in the presence of several

concentrations of pseudoephedrine (not shown). In

contrast, Britschgi et al. reported a positive in vitro

lymphoproliferative response to the culprit drugs in

several cases of AGEP.2 This apparent disagreement

may be due to the sensitivity of the assay. It is possible

that the drug-specific lymphocytes in peripheral blood

are below the detection limit of our proliferation assay

and ⁄ or that pseudoephedrine unmasks a hidden cuta-

neous epitope; thus, infiltrating T cells would recognize

the specific antigen in the skin but not in the in vitro

assay. Further studies are needed to clarify this point.

Acknowledgments

This work was supported by grants FIS01 ⁄ -0014-01

and FIS PI021027. We thank Ian Johnstone for help

with the English language version of the manuscript.

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� 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 139–142