Dapsone-induced hypersensitivity syndrome, hemolytic anemia, and severe agranulocytosis
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2 Case Report Dapsone-induced hypersensitivity syndrome, hemolytic anemia, and severe agranulocytosis Jemshad Alungal, Mansoor C Abdulla, Noorudheen Kaladi Kunnummal 1, Amrutha Sivadasan Department of General Medicine, M.E.S. Medical College, Perinthalmanna, Kerala, India, 1 Specialist, Geriatrics, Hamad Medical Corporation, Doha, Qatar Address for correspondence: Dr. Jemshad Alungal, Department of General Medicine, M.E.S. Medical College, Perinthalmanna , Kerala, India. jemshadalungal@gmail.com ABSTRACT Dapsone is used for the treatment of leprosy and a variety of blistering skin diseases. It may cause severe adverse drug reaction(s) with multiorgan involvement. We report the case of a 48-year-old female who developed dapsone hypersensitivity syndrome (DHS), hemolytic anemia, and severe agranulocytosis with secondary cavitating pseudomonal pneumonia due to dapsone. Key words: Agranulocytosis, cavitating pseudomonal pneumonia, dapsone, dapsone hypersensitivity syndrome (DHS), hemolytic anemia, pseudomonas INTRODUCTION Dapsone is used for the treatment of leprosy and a wide variety of dermatological inflammatory diseases such as dermatitis herpetiformis and chronic bullous dermatosis, Pneumocystis jiroveci pneumonia, in malaria prophylaxis. [1] Dapsone can cause a variety of adverse effects including hemolytic anemia, methemoglobinemia, hepatic involvement, cutaneous involvement (exanthematous eruption, Stevens- Johnson syndrome, or toxic epidermal necrolysis), agranulocytosis, nephritis, pneumonitis, and hypothyroidism. Dapsone hypersensitivity syndrome (DHS) [1] is a severe and distinct idiosyncratic adverse reaction with multiorgan involvement. CASE REPORT A 48-year-old female presented with high-grade fever, breathlessness, and cough with mucus expectoration for Access this article online Quick Response Code: Website: DOI: / days. Two months ago, she was started on dapsone (dosage: 100 mg twice daily) for bullous pemphigoid. She had no other significant past history. She had pallor, icterus, tender axillary lymphadenopathy, painful oral mucosal erosions, and healed pemphigoid lesions around her axilla and chest; she was also febrile and tachypneic. Her hemoglobin concentration was 8.8 g% (normocytic normochromic), total leukocyte count 190 cells/c.mm, differential count N 30% L 66% M 4%, platelet count 7.8 lakhs/c.mm, and erythrocyte sedimentation rate 30 mm in 1 h. Peripheral smear showed severe leukocytopenia, normocytic normochromic red blood cells (RBCs) with evidence of hemolysis and normal platelets [Figure 1]. Liver function test showed indirect hyperbilirubinemia with normal liver enzymes and hypoalbuminemia. Renal function test and urinalysis were normal. The X-ray of her chest showed bilateral interstitial pneumonia [Figure 2]. Serum lactate dehydrogenase (LDH) was 1,043 IU/L, and direct and indirect Coombs tests were negative. Her glucose-6- phosphate dehydrogenase (G6PD) level was normal. Study of her bone marrow revealed a marked reduction in the myeloid series [Figure 3]. Computed tomography (CT) of her thorax showed multiple irregular nodules in the lung parenchyma, with cavitation and enlarged cervical and mediastinal lymph nodes [Figure 4]. Study of her blood and sputum showed growth of pseudomonas. Serology for human immunodeficiency International Journal of Nutrition, Pharmacology, Neurological Diseases July-September 2015 Vol 5 Issue 3 113
3 Alungal, et al.: Dapsone induced hypersensitivity syndrome, hemolytic anemia and severe agranulocytosis Figure 1: Peripheral smear showing severe leukocytopenia and normocytic normochromic RBCs with spherocytes Figure 3: Bone marrow biopsy showing marked reduction in myeloid series [hematoxylin and eosin stain (H and E) 100 ] virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg), widal, dengue, and Leptospira were all negative. Axillary lymph node biopsy was normal. Acid-fast bacilli culture and bacterial and fungal culture of the biopsy specimen were negative. Her antinuclear antibody (ANA) profile was negative. Thus, a diagnosis of DHS and agranulocytosis with cavitating pseudomonal pneumonia was done. Dapsone was discontinued. She was treated with colony-stimulating factors, sensitive antibiotics, and oral corticosteroids. After 1 week of treatment, she became afebrile and her respiratory signs and symptoms improved. Investigations repeated after 2 weeks showed normal leukocyte count and hemoglobin level and her liver function tests were normal. DISCUSSION Dapsone is a potent antiparasitic and antiinflammatory compound mainly used in the treatment 114 Figure 2: X-ray of the chest showing bilateral interstitial pneumonia Figure 4: CT of the thorax showing multiple irregular nodules in the lung parenchyma with cavitation and enlarged cervical and mediastinal lymph nodes of leprosy and a variety of blistering skin diseases. However, the use of dapsone may be associated with a plethora of adverse effects like methemoglobinemia, bone marrow aplasia, hemolytic anemia, peripheral neuropathy, and the potentially fatal DHS. Dapsone is absorbed well from the gut and primarily metabolized through N-acetylation and N-hydroxylation. The hydroxylamine metabolite and other hydroxylated metabolites are potent oxidants and have been thought to cause the hematologic adverse effects associated with dapsone.[2] Individuals deficient in erythrocytic G6PD are at risk of severe and potentially fatal hemolysis due to dapsone. Dapsone-induced hemolytic anemia is mostly reported in patients with G6PD deficiency. The occurrence of hemolysis in patients with normal G6PD level suggests that hemolysis may be a doserelated event as may be seen with elevated dapsone International Journal of Nutrition, Pharmacology, Neurological Diseases July-September 2015 Vol 5 Issue 3
4 Alungal, et al.: Dapsone induced hypersensitivity syndrome, hemolytic anemia and severe agranulocytosis levels in patients with renal dysfunction or due to concurrent administration of medications that use the cytochrome P-450 isoenzyme system. There are reports of dapsone-induced hemolytic anemia in transplant recipients with normal G6PD levels. [3] All of them were receiving tacrolimus, which share the cytochrome P-450 isoenzyme system. Our patient did not have renal failure and was not on any drugs that share the cytochrome P-450 isoenzyme system. Alternatively, there may be mutations in the hexose monophosphate shunt or glutathione metabolism that lead to glutathione depletion and subsequent hemolysis, which may be possible in our case. [3] DHS is a rare, potentially fatal idiosyncratic systemic hypersensitivity syndrome characterized by fever, skin rash, eosinophilia, lymphadenopathy, hepatic, and pulmonary and other systemic manifestations that can lead to irreversible organ damage or even death if not recognized early and managed properly. [4] It can develop several weeks to as long as 6 months after the treatment initiation, and the reported incidence ranges 0.5-3%. [5] Anemia, oral erosions, conjunctivitis, splenomegaly, atypical lymphocytosis, and rise of liver enzymes are the other manifestations. All these features need not necessarily be present. Pathogenesis of DHS is unclear but the proposed mechanisms implicate metabolites of dapsone, which form haptens with the production of anti-dapsone antibodies. In addition to the factors responsible for hemolysis, modified graft-versus -host disease type of reaction, probably mediated by activated T cells, also plays a role in DHS. Aging and preexisting liver disease(s) offer relative protection against adverse effects because of the decreased enzyme activity and therefore, decreased production of toxic metabolites. Generally, DHS is self-limiting and most patients recover following the cessation of dapsone therapy and starting treatment with oral corticosteroids. The reaction is classified as dapsone syndrome when the symptoms start between the second and the eighth week of treatment and at least two of the following signs or symptoms are present: Fever, skin eruption, lymphadenopathy, and liver pathology (hepatomegaly, jaundice, and/or abnormal liver function tests). [6] Our patient had fever, severe oral erosions, and lymphadenopathy as the features of DHS and she improved with the administration of steroids. Hypoalbuminemia present in our patient is also a feature of dapsone hypersensitivity, which is probably due to the binding of dapsone to the circulating serum albumin. [7] Agranulocytosis is an acute condition where there is a sudden drop in white blood cell production, leaving the body susceptible to bacterial invasion and septicemia. It is a rare complication but exhibits very serious toxic effect(s) of the sulfones. It has been reported to occur in % of patients treated with dapsone. [8] Though reversible, this condition can be fatal due to the occurrence of septicemia or infections. In the majority of cases, its occurrence is due to sensitization to the drug that depresses the formation of granulocytes in the bone marrow. The mechanism postulated for the sensitization is the formation of hydroxylamine, the toxic metabolite of dapsone that is also responsible for methemoglobinemia and hemolysis. Another possible mechanism is the formation of antibodies for neutrophil progenitors in the bone marrow and the subsequent destruction, resulting in agranulocytosis. [9] Agranulocytosis due to dapsone is not dose-related and when severe, can involve the platelets. To detect the complication early, a leukocyte count with differential and hemoglobin levels should be done weekly for the first month of therapy, twice per month for the next 2 months, and periodically thereafter. Our patient had severe agranulolcytosis and she developed cavitating pseudomonal pneumonia secondary to this. Her neutrophil count improved with granulocytecolony stimulating factor (G-CSF). Case fatality rate in different reports has been 20%. Pseudomonas aeruginosa is one of the less common bacterial causes of necrotizing lung infection, leading to pulmonary cavitation. It occurs mainly in individuals with neutropenia and those who are immunocompromised, and the mortality rate is high. Our patient had severe neutropenia and she developed secondary pseudomonas aeruginosa pneumonia with lung cavitation, which improved completely with treatment. There are individual reports of DHS, hemolytic anemia, and agranulocytosis due to dapsone. Here, we report a patient with an array of complications due to dapsone, which to the best of our knowledge is the first such report. REFERENCES 1. Bucaretchi F, Vicente DC, Pereira RM, Tresoldi AT. Dapsone hypersensitivity syndrome in an adolescent during treatment of leprosy. Rev Inst Med Trop Sao Paulo 2004;46: Sago J, Hall RP. Dapsone. Dermatol Ther 2002;15: Lee SM, Geetha D. Dapsone induced hemolysis in a patient with ANCA associated glomerulonephritis and normal G6PD level and International Journal of Nutrition, Pharmacology, Neurological Diseases July-September 2015 Vol 5 Issue 3 115
5 Alungal, et al.: Dapsone induced hypersensitivity syndrome, hemolytic anemia and severe agranulocytosis implications for clinical practice: Case report and review of the literature. Springerplus 2015;4: Kosseifi SG, Guha B, Nassour DN, Chi DS, Krishnaswamy G. The dapsone hypersensitivity syndrome revisited: A potentially fatal multisystem disorder with prominent hepatopulmonary manifestations. J Occup Med Toxicol 2006;1:9. 5. Leslie KS, Gaffney K, Ross CN, Ridley S, Barker TH, Garioch JJ. A near fatal case of the dapsone hypersensitivity syndrome in a patient with urticarial vasculitis. Clin Exp Dermatol 2003;28: Grace M. An unusual case of dapsone syndrome. Indian Dermatol Online J 2011;2: Karp WB, Subramanyam SB, Robertson AF. Binding of dapsone and its analogues to human serum albumin. J Pharm Sci 1985;74: Bhat RM, Radhakrishnan K. A case report of fatal dapsone-induced agranulocytosis in an Indian mid-borderline leprosy patient. Lepr Rev 2003;74: Mishra M, Chhetia R. Dapsone-induced agranulocytosis in a patient of leprosy. Indian J Dermatol Venereol Leprol 2006;72: How to cite this article: Alungal J, Abdulla MC, Kunnummal NK, Sivadasan A. Dapsone-induced hypersensitivity syndrome, hemolytic anemia, and severe agranulocytosis. Int J Nutr Pharmacol Neurol Dis 2015;5: Source of Support: Nil. Conflict of Interest: None declared. Received: , Accepted: International Journal of Nutrition, Pharmacology, Neurological Diseases July-September 2015 Vol 5 Issue 3
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