A 50-Year-Old Male with Dapsone Hypersensitivity Syndrome

Dapsone, diamino-diphenyl sulfone, is an antibacterial and anti-inflammatory drug which is used worldwide for treating many diseases, such as leprosy, dermatitis herpetiformis, linear IgA bullous dermatosis, chronic bullous dermatosis of childhood, bullous eruption of systemic lupus erythematosus, erythema elevatum diutinum, leukocytoclastic vasculitis, polyarteritis nodosa and other kinds of vasculitis, prurigo nodularis, nodulocystic acne, cutaneous mycetoma, pustular psoriasis, malaria, pneumocystis carinii pneumonia etc. Since it is widely used, the adverse effects of this drug attract the attention of doctors from different specialities. Dapsone can cause several adverse effects, the most serious one is idiosyncratic systemic hypersensitivity syndrome, namely dapsone hypersensitivity syndrome (DHS), which is potentially fatal, characterized by fever, facial edema with infiltrated papules, generalized papulopustular or exanthematous rash which may extend to exfoliative dermatitis, eosinophilia, lymphadenopathy, hematologic involvement and organ involvement such as hepatitis, nephritis, pneumonitis, encephalitis, myocarditis occurring after 3–6 weeks of drug therapy. Here we have described a case of dapsone hypersensitivity syndrome developed after dapsone therapy for prurigo nodularis. The case is being reported to emphasize the need for timely diagnosis and prompt treatment of this rare complication for successful outcomes. Physicians should be aware of this infrequent but potentially fatal severe form of adverse reaction that can mimic other conditions.


Introduction
Dapsone hypersensitivity syndrome (DHS) can be considered as a manifestation of DRESS (drug rash with eosinophilia and systemic symptoms) syndrome. 1DRESS is an adverse reaction that can be seen with the use of many drugs such as dapsone, sulfonamides, allopurinol, cyclosporine, azathioprine, minocycline, antiviral drugs, anticonvulsant and gold salt. 2 DHS differs from other drug reactions because it can occur after prolonged exposure of offending drug and even up to 6 months after exposure.DHS is an idiosyncratic multi-organ disease.It has a frequency of 0.2-0.5% in patients on dapsone therapy. 1 DHS was described first by Allday, Lowe and Barnes as a hypersensitivity vasculitis syndrome.This syndrome typically presents with a triad of fever, skin eruption, and internal organ (lung, liver, neurological and other systems) involvement.Richardus and Smith proposed the following criteria to diagnose a case of dapsone hypersensitivity syndrome (DHS): [5][6][7][8] The exact mechanism behind DHS is not known.But few hypotheses have been proposed.Among these, it might be combination of type I and type IV, and perhaps type III hypersensitivity reactions.It could be a modified graft versus host disease mediated by activated T-lymphocytes. 9According to Prussick and Shear 10 , there are some evidences suggesting the metabolic differences in the production and detoxification of reactive metabolites which are important factors in sulfonamide hypersensitivity reactions.After absorption dapsone is metabolized in liver via N-acetylation and N-hydroxylation.N-acetylation has no relation with the adverse effects.However, hydroxylamine which is known as a toxic intermediate metabolite and formed by N-hydroxylation may cause hemolytic anemia and DHS.The metabolite can combine or modify some immunologically-significant chemicals, such as major histocompatibility complex (MHC), on the surface of the immune cells (antigen-presenting cells), then facilitate the T cells recognizing the antigen.Drugs are haptens which should be combined with proteins to form a complete antigen.The bioactivation and protein haptenation of sulphonamides, including sulfamethoxazole (SMX) and dapsone, produce the drug's metabolite and cellular protein forms a covalent product which induced the cellular toxicity. 10S are generally self-limiting reaction and respond well after withdrawl of dapsone and by starting oral or parenteral glucocorticoids (depending upon severity).Since dapsone persists up to 35 days in organs through protein binding and enterohepatic recirculation, slow tapering off of the corticosteroid therapy over at least one month with close monitoring of organ function is required.Abrupt discontinuation may cause a relapse.Nutritional support, fluid and electrolyte balance, control and prevention of infections (cellulitis, sepsis) and skin care are also required.Vitamin E supplement is found to be beneficial in dapsone induced hemolysis. 11

Case report
A 50-year-old hypertensive male recently diagnosed as a case of prurigo nodularis was prescribed 100 mg dapsone daily.After getting medication for one month he developed fever which was high grade, intermittent and was associated with chills and rigor.After seven days his body was studded with morbiliform eruption that progressed to generalized exfoliation in the next few days.He also developed yellowish coloration of sclera and urine and pruritus.Dapsone was stopped after 45 days of therapy.On physical examination, he was febrile (102 O F) and anemic.Pedal edema and painless inguinal lymphadenopathy were present.Skin evaluation revealed generalized erythema and scaling along with few erosions scattered all over the body.Multiple hyperpigmented nodules and pustules symmetrically distributed over both legs.Palms and soles showed epidermal detachment in the form of large sheets.Complete blood picture showed Hb 10.6 gm/dL, WBC 15×109/L, erythrocyte sedimentation rate 40 mm in the first hour, eosinophil 35% and platelet count 415×109/L.Liver function test revealed alkaline phosphatase 222 U/L, gamma glutamyl transferase (GGT) 97 U/L, aspartate aminotransferase (AST) 23 U/L, alanine aminotransferase (ALT) 22 U/L, prothrombin time 16.7 second, serum albumin 25 gm/L.Ultrasonography of abdomen revealed mildly enlarged prostate.Routine biochemical analysis showed random blood sugar 5.3 mmol/L and serum creatinine 2.44 mg/dL.Urine analysis showed pus cells 20−30/HPF, protein (+), epithelial cell 2-5/HPF and RBC 1-2/HPF.Pus for aerobic and anaerobic culture showed profound growth of Klebsiella species with sensitivity to cotrimoxazole, gentamicin, netilmicin, meropenem, and amikacin.Serum electrolyte showed sodium 130 mmol/L, potassium 5.1 mmol/L and chloride 98 mmol/L.Based on patient's medical history, clinical findings and laboratory tests, a diagnosis of DRESS was made.The patient was put on prednisolone 40 mg/day with H1 blocker, hydroxyzine and acetaminophen.Cefuroxime 500 mg 12 hourly was given initially, then intravenous meropenem was added in adjusted dose for renal impairment.His high temperature along with skin erosion and scaling subsided gradually and creatinine level became normal.Prednisolone was tapered to 30 mg after four weeks of therapy and continued to taper slowly in the following weeks.

Discussion
Vinod et al 11  There was a significant difference between the patients who recovered and those who died in the delay time from DHS onset to receiving treatment. 13he criteria for DRESS syndrome proposed by Bocquet et al 14 are as follows: 1) cutaneous drug eruption, 2) hematologic abnormalities, including eosinophilia greater than 1.5×109 eosinophils/L or the presence of atypical lymphocytes and 3) systemic involvement including adenopathy greater than two cm in diameter, hepatitis (liver transaminases values >2 N), interstitial nephritis, interstitial pneumonia, or carditis. 14These criteria emphasize two important characteristics -multiple organs involvement and eosinophilia.Our patient had an absolute eosinophil count of 5250/mm 3 with involvement of liver (cholestatic pattern) and kidney.Liver involvement displays a mixed hepatocellular and cholestatic pattern.Cholestatic pattern has a less severe course characterized by high ALT and moderate transaminase levels.Hepatitis may progress to liver failure.In the literature the dermatosis is not well-defined.Some authors describe it as a rash while others as a morbiliform rash or even as an exfoliative dermatitis.6][17] Our patient initially presented with generalized exanthem which progressed to a diffuse exfoliative dermatitis.
Dapsone is well-absorbed from the gut and primarily metabolized through N-acetylation and N-hydroxylation (oxidation).The hydroxylamine and the hydroxylated metabolites are potent oxidants and cause hematologic adverse effects, predominantly hemolysis.It is excreted by the kidney, but has significant enterohepatic circulation.It has a long elimination half-life of 24 to 30 hours on an average.Strong protein binding of the drug itself (70-90%) and its major metabolite, monoacetyldapsone (99%), contribute to the long half-life.Hypersensitivity reaction differs from other drug reactions and occurs during first six weeks of initiating the treatment to as late as six months.The side-effects are very low if plasma concentration of dapsone is below 5 mg/L. 18In our patient rashes appeared by the end of 5 weeks.

Conclusion
Generally DHS is a self-limiting drug reaction and most patients recover following cessation of dapsone therapy and starting treatment with oral corticosteroid.Mortality was reported to be 12-23% in severe DHS.Physicians, dermatologists, rheumatologists and leprologists prescribing dapsone for various clinical conditions should be aware of potentially fatal DHS to ensure timely diagnosis and appropriate management.
presented a 17-year-old male with complaints of high grade fever associated with chills and rigors, jaundice and itchy skin rash for 10 days.