Severe Dapsone Hypersensitivity Syndrome: Case Report

Case Report
Severe Dapsone Hypersensitivity

Syndrome
O Sener,1 L Doganci,2 M Safali,3 B Besirbellioglu,4 F Bulucu,5 A Pahsa 4
1
Division of Allergy, 2 Department of Microbiology and Clinical Microbiology, 3 Department of Pathology,
4
Department of Infectious Diseases, and 5 Department of Internal Medicine
Gulhane Military Medical Academy, Ankara, Turkey
Abstract. Dapsone, a potent antiparasitic and anti-inflammatory compound, is mainly used in the treatment of
leprosy and a variety of blistering skin diseases. It may cause a severe adverse drug reaction with multiorgan
involvement known as dapsone hypersensitivity syndrome. We report the case of a 21-year-old female patient
with dapsone hypersensitivity syndrome. The clinical presentation mimicked a viral exanthema.
Key words: Dapsone hypersensitivity. Dermatitis herpetiformis.
Resumen. La dapsona, un potente compuesto antiparasitario y antiinflamatorio, se utiliza principalmente para el

tratamiento de la lepra y diversas enfermedades cutáneas ampollosas. Puede causar una grave reacción adversa
con afectación multiorgánica denominada síndrome de hipersensibilidad a la dapsona. Presentamos el caso de una
paciente de 21 años de edad con síndrome de hipersensibilidad a la dapsona. Las manifestaciones clínicas imitaron
las de un exantema vírico.
Palabras clave: Hipersensibilidad a la dapsona. Dermatitis herpetiforme.
Introduction earlier. She was given a diagnosis of dermatitis

herpetiformis based on a skin biopsy, and she was given
Dapsone (4, 4’-diamino-diphenyl sulfone), a potent oral dapsone 100 mg/day by a dermatologist elsewhere.
anti-inflammatory and antiparasitic compound, is still She developed cyanosis on her lips, fingers, and toes
used as a first line drug for leprosy. In Europe and the within a week of starting therapy. Dapsone-induced
United States of America, however, it finds application methemoglobinemia was diagnosed and therapy was
mainly in the treatment of bullous dermatoses and stopped. Four weeks later, she consulted her primary care
dermatitis herpetiformis [1]. The most frequent side physician with complaints of high fever, malaise,
effects are dose-related methemoglobinemia and lymphadenopathy, maculopapular skin rash, and painful
hemolytic anemia, and rarely, it can cause an idiosyncratic oral mucosal lesions. She was referred to our infectious
reaction, called dapsone hypersensitivity syndrome diseases clinic with a suspected diagnosis of adult rubeola
(DHS). We report the case of a woman with DHS infection or infectious mononucleosis.
mimicking a viral exanthema. On admission, her temperature was 40 oC, blood
pressure was 100/60 mm Hg, and heart rate was 112
beats/min. She had bilateral conjunctivitis, periorbital
Case Description edema, and a pruritic maculopapular exanthematous rash
with pustules over her forehead, neck, trunk, back, and
A 21-year-old white Turkish woman was referred to extremities (Figure 1). Multiple bilateral cervical and
our infectious diseases clinic with suspicion of severe retroauricular lymph nodes measuring 1 to 2 cm and
measles or infectious mononucleosis. Her chief tender were noted. She had a 4-cm slightly tender enlarged
complaints were high fever lasting for 4 days associated liver below the costal margin. There was no splenomegaly
with malaise, sore throat, dysphagia, productive cough, or ascites. Her pharynx was hyperemic, and she had
and a pruritic rash. She reported having no important Stevens–Johnson-like lesions in the oral cavity. Lung and
health problem until intense pruritus started 6 months heart sounds were unremarkable except for slight
© 2006 Esmon Publicidad J Investig Allergol Clin Immunol 2006; Vol. 16(4): 268-270
269 O Sener et al
Figure 1. Pustular erythematous eruption on the third day

of hospitalization.
wheezing. She was hospitalized and blood samples were

taken for routine examination, including mononucleosis
and rubella–rubeola serology. All medications were
stopped and cold compresses were applied for the fever.
A complete blood count revealed hemoglobin 11.8 g,
hematocrit 32.6%, white blood cell count 26 600/mm3
(neutrophils 49%, lymphocytes 39% and monocytes
12%), platelet count 174 000/mm 3, and erythrocyte
sedimentation rate 20 mm in the first hour. Her liver
function tests were abnormal: direct bilirubin 1.4 mg/dL, Figure 2. Inflammatory cell infiltration especially in
indirect bilirubin 2.0 mg/dL, aspartate aminotransferase perivascular and periadnexal areas of the dermis
178 U/L, alanine aminotransferase 229 U/L, alkaline (hematoxylin and eosin stain; 40).
phosphatase 118 U/L, serum albumin 3.2 g/dL, and
prothrombin time 12 seconds. Viral hepatitis serology
(IgM antibody to hepatitis A antigen, hepatitis B surface focal parakeratosis, and focal vacuolar change in the basal
antigen, and hepatitis C antibody) were negative. layer. Morphologic findings were consistent with a
Although there was frank hematuria, the levels for urea, diagnosis of drug eruption, which was evaluated together
creatinine, uric acid, and electrolytes in blood were within with clinical history.
normal limits. Rubella–rubeola serology revealed high A diagnosis of DHS was thus based on the patient’s
specific IgG levels and were negative for specific IgM; medical history, clinical findings and laboratory test
so these viral infections were ruled out. A mononucleosis results. She was put on a gluten free diet, and
spot test was also negative. Levels of complement glucocorticoid therapy was started. Corticosteroids were
components C3 and C4 were low (C3, 44.5 mg/dL and given both orally (prednisolone 40 mg/d) and topically
C4, 4.0 mg/dL) and autoimmune screens consisting of (beclomethasone dipropionate ointment 0.025 %, 2 times
antinuclear, anti-double-stranded DNA, anti-smooth- a day). Cetirizine 10 mg/d and hydroxyzine 25 mg/d were
muscle, and anti-liver-kidney-microsome antibodies were added for pruritus. Her clinical condition improved
negative. Abdominal ultrasound showed uniform liver quickly, and laboratory test results returned to normal
enlargement with a slight increase in echo texture, and levels within 2 weeks. We planned to taper off her
there was no evidence of portal hypertension or biliary corticosteroid therapy over a period of 6 weeks and she
obstruction. Her chest radiograph was unremarkable and was discharged. After 8 weeks, her follow-up examination
blood cultures were negative. and laboratory results were normal.
Microscopic examination of the skin biopsy showed
moderate to severe mononuclear inflammatory cell
infiltration especially in perivascular, interstitial and Discussion
periadnexal areas of the dermis (Figure 2). Inflammatory
cell populations were rich in lymphocytes and eosinophils. Dapsone (4, 4’-diamino-diphenyl sulfone) is the parent
The epithelia of some hair follicles containing compound of sulfone drugs. Synthesized in 1908, its
inflammatory cells that were mostly neutrophils. Capillary antibacterial characteristics were not noticed until several
congestion, extravasation of erythrocytes and some decades later. Dapsone has been used as a first-line
melanophages were observed in the dermis. The epidermis treatment for leprosy since the 1950s [2]. It is also the
revealed focal and irregular acanthosis, mild spongiosis, drug of choice for the management of dermatitis
J Investig Allergol Clin Immunol 2006; Vol. 16(4): 268-270 © 2006 Esmon Publicidad
Severe Dapsone Hypersensitivity 270
herpetiformis. Although good results may be obtained for corticosteroids have been used to treat DHS; however,
some patients with a gluten-free diet, the difficulty of no comparative studies regarding their effectiveness have
dietary adherence makes dapsone the drug of choice for been performed to date. Since dapsone persists up to 35
many. Itching and blister formation can be controlled with days in organs through protein binding and enterohepatic
100 to 200 mg/d of dapsone in most [1]. recirculation, slow tapering off the corticosteroid therapy
Dapsone is absorbed well from the gut and primarily over at least 1 month with close monitoring of organ
metabolized through N-acetylation and N-hydroxylation function is required.
(oxidation) [3]. The hydroxylamine metabolite and other Generally DHS is a self-limiting drug reaction and
hydroxylated metabolites are potent oxidants and have most patients recover following cessation of dapsone
been thought to cause the hematologic adverse effects therapy and application of corticosteroid therapy;
associated with dapsone, including methemoglobinemia however, deaths have been reported [10]. Physicians,
and hemolytic anemia [3]. It is excreted by the kidney, but especially those dealing with leprosy treatment or working
has significant enterohepatic circulation [4]. Thus, a long in the fields of dermatology and allergy, should be aware
elimination half-life (between 24 and 30 hours on the of this infrequent but potentially fatal severe form of
average) is important to remember in case adverse reactions adverse reaction that can mimic other conditions.
emerge after a long metabolite impact period [4].
Several drugs, including anticonvulsants,
sulfonamides, dapsone, allopurinol, and minocycline, may References
cause a severe hypersensitivity syndrome that consists of
fever, rash, lymphadenopathy and different degrees of 1. Leonard JN, Fry L. Treatment and management of dermatitis
organ involvement. This entity is also termed drug herpetiformis. Clin Dermatol. 1991;9:403-8.
reaction with eosinophilia and systemic symptoms 2. Lowe J. Treatment of leprosy by diamine diphenyl sulfone
(DRESS) [5], and DHS has been considered a by mouth. Lancet. 1950;1:145-50.
3. Sago J, Hall III RP. Dapsone. Dermatol Ther. 2002;15:340-
manifestation of DRESS syndrome. Typically the
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symptoms begin within several weeks of commencing 4. Zuidema J, Hilbers-Modderman ESM, Merkus FWHM.
therapy. Patients present with fever, malaise, a generalized Clinical pharmacokinetics of dapsone. Clin Pharmacokinet.
cutaneous eruption, lymphadenopathy, hemolytic anemia, 1986;11:299-315.
and hepatitis. The rash, which is often initially a benign 5. Gruchalla RS. Drug allergy. J Allergy Clin Immunol.
morbilliform eruption, may develop into frank exfoliative 2003;111(2):S548-59.
dermatitis [3, 5-7]. Liver involvement displays a mixed 6. Prussick R, Shear NH. Dapsone hypersensitivity syndrome.
hepatocellular and cholestatic pattern [6] although drug- J Am Acad Dermatol. 1996;35:346-9.
induced cholangitis has been reported in a patient with 7. Leslie KS, Gaffney K, Ross CN, Ridley S, Barker TH,
DHS [8]. According to Richardus and Smith [9], a true Garioch JJ. A near fatal case of the dapsone hypersensitivity
syndrome in a patient with urticarial vasculitis. Clin Exp
diagnosis of DHS should be made based on the following Dermatol. 2003;28(5):496-8.
criteria: a) symptoms manifesting within 8 weeks of 8. Itha S, Kumar A, Dhingra S, Choudhuri G. Dapsone induced
starting therapy and resolving after withdrawal of the drug, cholangitis as a part of dapsone syndrome: a case report.
b) symptoms not attributable to any other drug used BMC Gastroenterol. 2003;3(1):21.
simultaneously, and c) symptoms unrelated to leprosy or 9. Richardus JH, Smith TC. Increased incidence in leprosy of
any underlying disease. hypersensitivity reactions to dapsone after introduction of
It is presumed that hydroxylated metabolites are multidrug therapy. Lepr Rev. 1989;60:267-73.
important in the pathogenesis of DHS. A reduction in N- 10. Lau G. A fatal case of drug-induced multi-organ damage in
hydroxylation enzyme levels or activity results in a patient with Hansen’s disease: dapsone syndrome or
rifampicin toxicity? Forensic Sci Int. 1995;73(2):109-15.
decreased total clearance of dapsone [6]. Aging or
preexisting liver disease may offer relative protection
against adverse effects because of decreased enzyme
activity and, therefore, decreased production of toxic
metabolites [6]. The long elimination half-life that
Osman Sener
averages between 24 and 30 hours is thought to be due to
significant enterohepatic recirculation of the drug [3]. Gulhane Military Medical Academy
Strong protein binding of the drug itself (70%-90%) and Division of Allergy
its major metabolite, monacetyl dapsone (99%), 06018 Etlik, Ankara, Turkey
contribute to that long half-life [4]. Systemic E-mail: [email protected]
© 2006 Esmon Publicidad J Investig Allergol Clin Immunol 2006; Vol. 16(4): 268-270

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Case Report

Severe Dapsone Hypersensitivity

Key words: Dapsone hypersensitivity. Dermatitis herpetiformis.

Resumen. La dapsona, un potente compuesto antiparasitario y antiinflamatorio, se utiliza principalmente para el

Palabras clave: Hipersensibilidad a la dapsona. Dermatitis herpetiforme.

Introduction earlier. She was given a diagnosis of dermatitis

Figure 1. Pustular erythematous eruption on the third day

wheezing. She was hospitalized and blood samples were

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