Acute generalized exanthematous pustulosis due to oral use of blue dyes.
ABSTRACT Acute generalized exanthematous pustulosis is a rare severe pustular cutaneous adverse reaction characterized by a rapid clinical course with typical histological findings. It is accompanied by fever and acute eruption of non-follicular pustules overlying erythrodermic skin. The causative agents are most frequently antibacterial drugs. We present a patient with acute generalized exanthematous pustulosis caused by methylene blue and indigotin dyes.
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ABSTRACT: This article updates current knowledge on hypersensitivity reactions to diagnostic contrast media and dyes. After application of a single iodinated radiocontrast medium (RCM), gadolinium-based contrast medium, fluorescein, or a blue dye, a hypersensitivity reaction is not a common finding; however, because of the high and still increasing frequency of those procedures, patients who have experienced severe reactions are nevertheless frequently encountered in allergy departments. Evidence on allergologic testing and management is best for iodinated RCM, limited for blue dyes, and insufficient for fluorescein. Skin tests can be helpful in the diagnosis of patients with hypersensitivity reactions to these compounds.Immunology and Allergy Clinics of North America. 08/2014; 34(3):547–564.
korean j intern med 2011;26:360-363
pISSN 1226-3303 eISSN 2005-6648
acute Generalized exanthematous pustulosis Due to oral
Use of Blue Dyes
osman sener1, Ösman Kose2, Özgür Kartal1, and Mukerrem safali3
1Division of Allergy, Department of Internal Medicine, Departments of 2Dermatology and 3Pathology, Gülhane Military Medical
Academy and Medical School, Ankara, Turkey
Acute generalized exanthematous pustulosis is a rare severe pustular cutaneous adverse reaction characterized by
a rapid clinical course with typical histological findings. It is accompanied by fever and acute eruption of non-follicular
pustules overlying erythrodermic skin. The causative agents are most frequently antibacterial drugs. We present a patient
with acute generalized exanthematous pustulosis caused by methylene blue and indigotin dyes.
Keywords: Methylene blue; Indigofera; Drug eruptions
Acute generalized exanthematous pustulosis (AGEP)
is a rare and severe cutaneous hypersensitivity reaction
pattern that resembles pustular psoriasis. In over 90%
of cases, the causative agents are systemic drugs, par-
ticularly anti-infectious agents such as aminopenicillins
and macrolides . Antifungal agents, non-steroidal anti-
inflammatory drugs, analgesics, antiarrhythmics, anticon-
vulsants, and antidepressants may also be responsible. In
addition to drugs, other triggers have also been identified
including exposure to mercury and viral infections [1,2].
Proposed diagnostic criteria include 1) acute develop-
ment of numerous, small (< 5 mm), mainly nonfollicular
pustules arising on widespread edematous erythema; 2)
fever > 38ºC; 3) neutrophilia with or without mild eosino-
philia; 4) spontaneous resolution of pustules in < 15 days; 5)
subcorneal or intraepidermal pustules on a skin biopsy .
We describe the first reported case of AGEP associated
with blue-dye hypersensitivity.
A 69-year-old male was referred to our clinic because of
generalized pruritus and erythema accompanied by high
fever. He had a history of hypertension for 20 years and
had been taking 16 mg candesartan cilexetil tablets. The
day before admission, he was given tablets three times
daily for dysuria that included helmitol, methylene blue,
and indigotin. On physical examination, his body temper-
ature was 37ºC. He had pruritic erythematous lesions on
the trunk and upper extremities. He was diagnosed with
a drug reaction due to the drug used for dysuria. The drug
was discontinued, and he was given oral antihistamine
therapy. After 24 hours, he was admitted with complaints
Received : september 29, 2009
Revised : november 2, 2009
Accepted : november 18, 2009
Correspondence to Özgür Kartal, M.D.
Division of Allergy, Department of Internal Medicine, Gülhane Military Medical Academy and Medical School, Gülhane Askeri Tıp Akademisi, Allerjik
Hastalıklar BD, 06018, Ankara, Turkey
Tel: 90-312-304-4133, Fax: 90-312-304-4139, E-mail: firstname.lastname@example.org
Copyright © 2011 The Korean Association of Internal Medicine
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sener O, et al. Acute generalized exanthematous pustulosis due to oral use of blue dyes 361
of high fever (40ºC), increased number of skin lesions,
arthralgia, and headache. A dermatological examination
revealed exanthema over 60% of the body accompanied
by angioedema of the lips and eyelids. The rash was com-
posed of scattered nonfollicular small pustules over an
erythematous background (Fig. 1). No ocular or mucous
membrane symptoms were present. He was clinically di-
agnosed with AGEP and hospitalized. A pustule culture
was free of organisms. The only abnormal laboratory find-
ing was blood eosinophilia (1.25 × 109/L). Other laboratory
test results, such as a neutrophil count and serological re-
sults were within normal limits. A punch biopsy was taken
from the erythematous and pustular skin area. A histo-
pathological examination of the skin biopsy revealed sub-
corneal/superficial intraepidermal pustule formation and
a collection of neutrophils including eosinophils. Some
neutrophilic exocytosis and mild spongiosis was present
around the pustules in the epidermis. The upper dermis
was edematous and contained a moderate inflammatory
cell infiltrate with some eosinophils in the perivascular ar-
eas (Fig. 2). The histopathological diagnosis was consistent
with AGEP. He was administered an antihistamine tablet
(5 mg/day levocetirizine) and both oral (48 mg/day meth-
ylprednisolone) and topical (methylprednisolone acetate)
corticosteroid therapy. Omeprazol (20 mg, bid) was added
to his therapy regimen. On the second day of hospitaliza-
tion, he reported bloody feces.
An esophagogastroduodenoscopy showed disseminated
erosive gastritis of the stomach mucosa.
The pustular skin lesions and systemic findings
resolved within 48 hours of hospitalization, and a second
endoscopic examination was normal. Oral corticosteroid
therapy was stopped on the fifth day. He continued to
take his previous antihypertensive therapy (candesartan
cilexetil) without any adverse reactions. He has not taken
any other medications or any drug or food containing
methylene blue or indigotin dye. He was discharged
without antihistamine or corticosteroid therapy and
invited to follow-up visits. Skin lesions and systemic
symptoms had cleared up completely on day 20 after his
At the third examination 2 months after discharge, he
disclosed that he had accidentally used another drug for
dysuria containing helmitol. However, he did not report
any adverse reactions such as those reported previously.
Therefore, helmitol was omitted from the skin tests.
Figure 1. Pustules on diffuse erythema. Multiple pustular lesions
on an erythematous background.
Figure 2. The histopathological diagnosis was consistent with
acute generalized exanthematous pustulosis. A skin biopsy showed
subcorneal/superficial intraepidermal pustule formation and a
collection of neutrophils, including eosinophils. (A) Superficial
epidermal pustulation (H&E, × 40). (B) Neutrophilic spongiosis
(H&E, × 100).
362 The Korean Journal of Internal Medicine Vol. 26, No. 3, september 2011
Skin prick tests were performed at 2 months after
discharge using methylene blue and the coloring agent of
the tablets, indigotin, diluted in water. The prick test was
negative. Patch tests were performed with the same agent
diluted to 20% in petrolatum. Patch tests were read 48 and
72 hours after application and were negative.
Methylene blue and indigotin are dyes are currently used
as a tracer for detecting urinary and digestive fistulas, for
assessing tubal permeability, or in sentinel lymph node
Methylene blue is used as a treatment for some clinical
conditions and for diagnostic purposes; it is an alternative
choice for treating hypotension during septic shock and
for treating anaphylaxis, depending on the radiocontrast
material, to balance arterial blood pressure . It can also
be used at lower doses to treat methemoglobinemia .
Indigo, which is produced by fermenting the Indigofera
tinctoria plant, has been used as a dye in denims, blue
jeans, and other fabrics. Indigotin and indigocarmine
are indigo derivatives that are widely used as synthetic
coloring agents in the food and cosmetic industries in
many countries. Moreover, indigocarmine is considered
biologically inert and extremely safe.
Many case reports of allergic adverse reactions to blue
dyes have been described. The symptoms vary from
urticaria to anaphylaxis [9-11].
The physiopathological mechanisms of AGEP remain
uncertain, but drug-specific positive patch test responses
and in vitro lymphocyte proliferative responses in patients
with a history of AGEP strongly suggest that this adverse
cutaneous reaction occurs via a drug-specific T-cell-
mediated process .
Viral infections are the cause of most drug eruptions in
children, whereas drugs are more frequently responsible
in adults . In this case, the history and clinical course
were consistent with a drug reaction; therefore, we did not
conduct serological test to determine a viral etiology.
It may be clinically difficult to distinguish AGEP from
other pustular dermatoses, and a histopathological
examination is helpful. A histological analysis reveals
subcorneal and/or intraepidermal spongiform pustulation
and subcorneal collections of neutrophils with papillary
dermal edema and a perivascular infiltrate consisting of
neutrophils and sometimes eosinophils.
Pustules are commonly localized in the main folds
(neck, axillae, and groin), trunk, and upper extremities.
Additional skin symptoms, such as edema of the face and
hands, purpura, vesicles, blisters, and “atypical” targets,
may also be present. Mucous membrane involvement is
rare, usually mild, and generally restricted to the oral
mucosa. The clinical course of the skin reaction is very
typical. The time interval between drug administration
and skin eruption is normally less than 2 days. Skin
symptoms usually resolve within a few days without
No specific treatment is recommended for AGEP except
supportive care according to the clinical situation. It is a
self-limited disease with a favorable prognosis.
However, AGEP may be potentially life threatening,
particularly in older patients. The mortality rate of AGEP
is approximately 2% . Therefore, identifying and
promptly removing the culprit drug is important.
Patch testing may sometimes contribute to an AGEP
diagnosis; however, it did not help in this case. The
sensitivity of patch testing to drugs responsible for AGEP
is approximately 50% .
We report an interesting case of pustular eruption that
presented with nonfollicular sterile pustules with diffuse
edema and erythema on the face, trunk, intertriginous
areas, and extremities in association with a high fever.
Although there are cases of dermatological symptoms
due to blue dyes, this is the first case report of AGEP due to
blue dyes [9-11]. Our AGEP diagnosis, which was aided by
a skin biopsy and clinical findings, was confirmed.
Although skin epidermal prick test and patch test results
did not support our diagnosis, similar negative test results
have been reported in some previous cases of drug-related
AGEP. This can be explained by the activation of different
immunological mechanisms based on the difference in the
entrance and contact of the drugs. Positive skin test results
are not a typical finding of AGEP.
Conflict of interest
No potential conflict of interest relevant to this article
Sener O, et al. Acute generalized exanthematous pustulosis due to oral use of blue dyes 363
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