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C C C C C A A A A A S S S S S E E E E E R R
R E E E E E P P P P P O O O O O R R R R R T T T T T S S S S S
Azathioprine Hypersensitivity Presenting as Sweet Syndrome in a Child
with Ulcerative Colitis
MI JIN KIM, *KEE TAEK JANG, AND YON HO CHOE
From the Departments of Pediatrics and *Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine,
Sweet syndrome is a cutaneous lesion characterized by tender, red inflammatory
nodules or papules. We describe a pediatric case of Sweet syndrome presenting
10 days after treatment with azathioprine. As azathioprine is widely used in children
with inflammatory bowel disease, clinicians should be aware of this unusual
Key words: Azathioprine, Children, Hypersensitivity, Sweet syndrome.
Yon Ho Choe, Department of Pediatrics,
Samsung Medical Center,
Sungkyunkwan University School of
Medicine, 50 Irwon-dong, Gangnam-gu,
Seoul, 135-710, South Korea.
Received: June 10, 2010;
Initial Review: July 01, 2010;
Accepted: August 05, 2010.
It can become generalized, and patients often are ill with
associated signs and symptoms, including malaise, high
fever, neutrophilia, elevated erythrocyte sedimentation
rate and C-reactive protein levels, which mimic an
infectious process. It has rarely been seen as a mani-
festation of azathioprine hypersensitivity in adults [1-4].
weet syndrome, or acute febrile neutrophilic
dermatosis, is a cutaneous lesion characterized
by tender, red inflammatory nodules or papules,
usually affecting the upper limbs, face and neck.
A nine-year-old girl was referred for management of
refractory ulcerative Colitis (UC) that had been diagnosed
one year previously. She had no history of reported drug
allergies and had been prednisolone-dependent (2 mg/kg/
day) for much of the preceding year, with her disease
flaring after attempts to reduce the prednisolone dosage.
During the hospitalization, she received mesalazine
treatment (48 mg/kg/day) without prednisolone, but it was
ineffective. She underwent azathioprine therapy (1 mg/kg/
day) and 10 days later was hospitalized for fever
(temperature of 39.2ºC), skin rash and hematochezia.
Physical examination was significant for numerous
erythematous, painful, 1-3 mm vesicular lesions with
central pustules on her face and both arms (Fig. 1).
Laboratory results showed an elevated white blood cell
count (13,470/μL) with neutrophilia, microcytic
hypochromic anemia (hemoglobin 9.2 g/dL, MCV 80.9 fl,
MCH 24.8 pg), hyponatremia (132 mmol/L), and a
markedly raised erythrocyte sedimentation rate (89 mm/
hr) and C-reactive protein level (3.13mg/dL). Anti-nuclear
antibody was negative, but c-type anti-neutrophil
cytoplasmic antibody (c-ANCA) was positive. Her
thiopurine methyltransferase (TPMT) activity was normal
(18.2 U/ml RBC, reference range: 15.1-26.4 U/mL RBC).
Blood cultures and urinalysis were obtained and the
patient was started on cefotaxime (100 mg/kg/day) for a
possible infectious etiology.
Two days after the cefotaxime treatment, the patient
still had a fever. The patient then received metronidazole
(30 mg/kg/day) for a week and prednisone (1.7 mg/kg/
day). However, she was febrile with shaking chills and
nausea. Cultures taken from blood and urine prior to
antibiotic therapy were sterile. Biopsy specimens and
tissue cultures were taken from the pustular lesions.
Pathologic evaluation of skin biopsy showed massive
neutrophilic infiltrate in the entire dermis (Fig. 1). Tissue
culture results were negative for bacterial or fungal
infection. Based on the clinical course, a diagnosis of
sweet syndrome was made. As the patient’s fever had not
subsided in spite of the administration of antibiotics and
steroid, we presumed that the sweet syndrome was caused
by the azathioprine and was not due to inflammatory bowel
disease. The azathioprine therapy was discontinued.
Within 48 hours, the patient’s fever abated and her skin
lesions improved. Following this improvement, the
970VOLUME 48__DECEMBER 17, 2011
prednisolone dose was reduced to 0.4 mg/kg per day
without a recurrence of her symptoms.
At follow-up after two weeks, there had been no
recurrences of her symptoms, and her UC was
comparatively well controlled by prednisolone and
The criteria for drug-induced SS have been reviewed by
many authors [3,5] and include abrupt onset of painful
erythematous plaques or nodules, histopathologic
evidence of a dense neutrophilic infiltrate without
evidence of leukocytoclastic vasculitis, pyrexia
(temperature >38ºC), and a temporal relationship between
drug ingestion and clinical presentation, as well as
resolution after withdrawal. Our patient meets most of
ANCAs have been described in some cases, and may
be pathogenically relevant through the activation of
neutrophils . In our case, c-ANCA was positive.
Kemmett, et al.  reported the presence of c-ANCA in six
of the seven patients with sweet syndrome and speculated
whether ANCA may be helpful in establishing the
diagnosis of sweet syndrome .
Azathioprine is a widely used immunosuppressive
agent that has been used increasingly as a steroid-sparing
agent for the treatment of Crohn’s disease and UC.
Azathioprine rarely causes a hypersensitivity syndrome
which is characterized by fever, headache, arthralgias, and
rash, with possible cardiovascular, renal, lung, and hepatic
involvement . Skin lesions include erythematous or
maculopapular eruptions, vesicules or pustules, urticaria,
purpuric lesions, erythema multiforme, or erythema
nodosum. A case of acute generalized exantematous
pustules induced by azathioprine like our case also has
been reported . Diagnosis is often missed or delayed, as
the clinical features are often misinterpreted as either
sepsis or an exacerbation of the underlying disease state.
According to previous studies , TPMT activity was not
predictive of this type of adverse effect.
The morphology of these skin lesions can mimic that
of several other mucocutaneous and systemic conditions.
The differential diagnosis includes infectious and
inflammatory disorders, neoplastic conditions, reactive
erythemas, vasculitis. Skin lesions and negative cultures
help in the diagnosis. In addition, negative test results for
autoimmune diseases are important for diagnosis. In our
case, an infection focus or signs of an autoimmune disease
could not be detected. Clinical and histopathologic
findings supported the drug-induced sweet syndrome and
cessation of the drug caused a rapid regression in
symptoms. In patients without prior exposure to
azathioprine, signs and symptoms usually begin
approximately two weeks from the initial azathioprine
exposure , which began after 10 days in this child.
We believe that azathioprine-induced sweet syndrome
may be under-diagnosed because it can easily be
misinterpreted as inflammatory bowel disease-related skin
Contributors: All authors contributed to case work-up and
drafting the manuscript.
Competing interests: None stated.
1. Garey KW, Streetman DS, Rainish MC. Azathioprine
hypersensitivity reaction in a patient with ulcerative colitis.
Ann Pharmacother. 1998;32:425-8.
2. Paoluzi OA, Crispino P, Amantea A, Pica R, Iacopini F,
Consolazio A, et al. Diffuse febrile dermatosis in a patient
with active ulcerative colitis under treatment with steroids
and azathioprine: a case of Sweet’s syndrome. Case report
and review of literature. Dig Liver Dis. 2004;36:361-6.
3. El-Azhary RA, Brunner KL, Gibson LE. Sweet syndrome
as a manifestation of azathioprine hypersensitivity. Mayo
Clin Proc. 2008;83:1026-30.
4. Yiasemides E, Thom G. Azathioprine hypersensitivity
presenting as a neutrophilic dermatosis in a man with
ulcerative colitis. Australas J Dermatol. 2009;50:48-51.
5. Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome.
6. Sarkany RP, Burrows NP, Grant JW, Pye RJ, Norris PG.
The pustular eruption of ulcerative colitis: a variant of
Sweet’s syndrome? Br J Dermatol. 1998;138:365-6.
7. Kemmett D, Harrison DJ, Hunter JA. Antibodies to
Fig. 1 Pustular and crust lesions surrounded by erythema
appeared on face (a) and arm (b) 10 days after
administration of azathioprine. (c) Skin biopsy of
pustular lesion shows massive neutrophilic infiltration in
entire dermis (H&E, x400).
971VOLUME 48__DECEMBER 17, 2011
H1N1 Infection in children with Hematological Malignancies
PRABHAT S MALIK, *SHOBHA BROOR AND SAMEER BAKHSHI
From the Departments of Medical Oncology and *Microbiology, Dr BRA Institute Rotary Cancer Hospital, and All India Institute of
Medical Sciences4, New Delhi 110 029, India.
In the recent pandemic of H1N1 infection, pediatric patients with haematological
malignancies were considered high risk for severe illness. There is paucity of data
regarding course of H1N1 infection in this subgroup. We describe H1N1 infection
in 3 children with acute leukemia. All three patients presented with neutropenic
fever; 2 had probable fungal pneumonia based on chest imaging and
galactomanan estimation. Diagnosis of H1N1 infection was delayed in all 3
patients as it was not suspected initially. One patient died despite treatment. H1NI
infection may coexist with other infections in febrile neutropenia.
Key words : H1N1 infection, Hematological malignancies, Pneumonia.
Dr Sameer Bakhshi,
Additional Professor of Pediatric
Oncology, Department of Medical
Oncology, Dr BRA Institute Rotary
Cancer Hospital, AIIMS, New Delhi
Received: June 22, 2010;
Initial Review: July 14, 2010;
Accepted: August 5, 2010.
immunosuppression . In India, till now there have been
31866 confirmed cases and 1517 deaths of lab confirmed
cases . We describe the diagnostic challenges, course
and outcome of H1N1 infection in three children with
different hematological malignancies.
isk factors for severe illness and death due to
H1N1 infection include young children,
obesity, chronic lung disease, pregnancy, heart
disease, neurocognitive disorders and
We had three patients with different haematological
malignancies in varied phases of treatment who were
found to have H1N1 infection between December 2009
and March 2010. The clinical details are shown in Table I.
Diagnosis of H1N1 infection was based on quantitative
polymerase chain reaction from nasopharyngeal swabs.
Chest radiological findings
aspergillosis in two patients. Galactomanan assay was also
supporting fungal infection in these patients thereby
suggesting a diagnosis of probable invasive aspergillosis.
Bronchoalveolar lavage could be performed in only one
patient (patient 3) who grew Pseudomonas species in the
lavage fluid. All children were neutropenic at the onset of
symptoms. One patient (patient 1) died due to respiratory
failure and shock. In this patient, there was a delay of more
than 10 days to initiate treatment with oseltamivir, H1N1
infection was not suspected initially. The diagnosis and
treatment of H1N1 infection was delayed in patient 3 also,
but he improved with treatment as his disease was in
remission and total leucocyte counts and neutrophil counts
were showing on improving trend.
It is interesting to study the course of this infection during
the recent pandemic in this subgroup of patients as
pediatric age group and malignancies both are considered
to be risk factors for severe illness due to this infection.
Patients with hematological malignancies are expected to
have more morbidity and mortality due to the already
compromised immunity, associated neutropenia, and
coexistent bacterial and fungal infections. Usually a
diagnosis of bacterial infection is considered in the setting
of neutropenic fever and thereafter a fungal infection is
considered if fever persists. It is for this reason that the
diagnosis of H1N1 infection was not considered initially in
our patients. The diagnosis was further delayed due to the
radiological features being suggestive of invasive fungal
infection in two patients. It is possible that H1N1 could
have been a coexistent infection with other usual infections
neutrophil cytoplasmic antigens: serologic marker for
Sweet’s syndrome. J Am Acad Dermatol. 1991;24: 967-9.
8. El-Azhary RA. Azathioprine: current status and future
considerations. Int J Dermatol. 2003;42:335-41.
9. Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute
generalized exanthematous pustulosis associated with
azathioprine hypersensitivity. Clin Exp Dermatol.
10. McGovern DP, Travis SP, Duley J, Shobowale-Bakre el M,
Dalton HR. Azathioprine intolerance in patients with IBD
may be imidazole-related and is independent of TPMT
activity. Gastroenterology. 2002;122:838-9.