Dapsone Induced Hypersensitivity Syndrome: A Rare Case Report

Diagnostic assessment

Laboratory tests revealed anemia (Hb 11 g/dL), markedly elevated aspartate transaminase (AST) and alanine transaminase (ALT), hypoalbuminemia, and hyperbilirubinemia. Viral hepatitis, HIV, and malaria were excluded. Ultrasound confirmed hepatomegaly and splenomegaly with otherwise normal abdominal findings.

Therapeutic intervention and outcome

MDT was discontinued, and intravenous dexamethasone was initiated, followed by oral prednisolone tapering. Supportive therapy included paracetamol, vitamins, fluids, and antibiotics. Clinical improvement was noted with resolution of fever and skin changes, and normalization of laboratory parameters. The patient was discharged after 2 weeks [Figure 2].

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Figure 2:

Skin changes on Day 14 at discharge. (a) Back view, (b) Front view; By the time of discharge, the patient showed marked improvement. The generalized exfoliation and erythema observed at admission had subsided, with resolution of scaling and redness. These findings reflect clinical recovery following discontinuation of dapsone and initiation of corticosteroid therapy.

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Pharmacokinetics of MDT drugs

Dapsone is efficiently absorbed orally (70–100% bioavailability), widely distributed, and undergoes hepatic metabolism via acetylation and hydroxylation.⁴ Hydroxylamine metabolites drive hemolysis, methemoglobinemia, and DHS. Genetic variability in acetylation influences susceptibility, while enterohepatic recirculation prolongs its half-life, allowing adverse effects to persist even after discontinuation. Monitoring hemoglobin, bilirubin, liver enzymes, and G6PD status is essential before therapy.

Rifampicin is rapidly absorbed, reaching peak plasma levels in 2–4 hours. Absorption is reduced by food, so administration on an empty stomach is advised. It is widely distributed, penetrates cerebrospinal fluid, and undergoes hepatic deacetylation.⁵ As a potent inducer of cytochrome P450 enzymes, rifampicin causes significant drug–drug interactions. Excretion is mainly biliary, with autoinduction shortening its half-life during chronic use. Vigilance for hepatotoxicity and drug interactions is crucial.

Clofazimine shows variable absorption (45–70%), enhanced by fatty meals. Its lipophilic nature leads to accumulation in adipose tissue, skin, liver, and spleen, explaining both sustained therapeutic effect and characteristic pigmentation.⁶

Metabolism is slow, excretion occurs mainly via bile, and the half-life is about 70 days. Persistent pigmentation and gastrointestinal intolerance may continue even after discontinuation.

Clinical evidence and therapeutic applications

Dapsone has broad antimicrobial activity, is effective against Mycobacterium leprae and M. ulcerans, and, at higher concentrations, against M. tuberculosis (including resistant strains) and members of the Mycobacterium avium complex.⁷ Beyond leprosy, dapsone has been combined with pyrimethamine for malaria prophylaxis, particularly in chloroquine-resistant Plasmodium falciparum and P. vivax. Other combinations (chlorproguanil–dapsone, artesunate–dapsone–proguanil) have also been used in the treatment of malaria.

In dermatology, dapsone is used as adjuvant therapy, often combined with corticosteroids, in the treatment of pemphigus vulgaris. In AIDS patients, dapsone–pyrimethamine regimens have been used to treat opportunistic infections such as Pneumocystis jirovecii pneumonia and Toxoplasma gondii encephalitis, and even Kaposi’s sarcoma. Importantly, dapsone also exhibits anti-inflammatory activity independent of its antimicrobial effects, leading to its use in conditions such as dermatitis herpetiformis, rheumatoid arthritis, acne conglobata, chronic urticaria, vasculitis, bullous systemic lupus erythematosus, and Behçet’s disease.⁸

Mechanistically, dapsone modulates polymorphonuclear leukocytes (PMNs), affecting migration and apoptosis. It inhibits neutrophil chemotaxis, reduces reactive oxygen intermediates, and interferes with G-protein activation. In urticaria, its effects are mediated by downregulation of leukotriene B4 and interference with CD11B expression. Additional studies suggest inhibition of lymphocyte transformation, suppression of complement activation, and interference with the myeloperoxidase–halide cytotoxic system.

Adverse effects

Although generally considered safe, dapsone is associated with multiple adverse effects. Gastrointestinal disturbances (abdominal pain, anorexia, vomiting) are common. Less frequent but serious complications include pulmonary eosinophilia, hepatitis, nephrotic syndrome, renal papillary necrosis, peripheral neuropathy, and muscle weakness.⁹

Hematological toxicity is significant. Hydroxylamine metabolites induce methemoglobinemia, hemolysis, and agranulocytosis. Antioxidants such as vitamins C and E may mitigate these effects. Methemoglobinemia often presents with a “saturation gap” between arterial blood gas results and pulse oximetry readings. Management involves discontinuation of dapsone, supportive care, and methylene blue if levels exceed 30%. Patients with G6PD deficiency are at particular risk, underscoring the importance of pre-treatment screening.

Cutaneous and immunologic reactions include exfoliative dermatitis, erythema multiforme, urticaria, erythema nodosum, toxic epidermal necrolysis, and drug-induced lupus erythematosus. DHS remains the most serious, with an incidence of 0.5–3% and mortality rates of 12–23%. Management requires immediate withdrawal of dapsone and systemic corticosteroids, with tapering extended beyond one month due to the drug’s long half-life.

Special considerations in pregnancy and pediatrics

Dapsone crosses the placenta and is detected in breast milk, raising concerns about neonatal hemolysis and cyanosis. It is classified as a Category C drug in pregnancy, meaning potential harm has been observed in animal studies and limited human data. Use should be restricted to situations where benefits outweigh risks, with close monitoring of the mother and infant.

In children, dapsone is considered safe when appropriately dosed (2 mg/kg/day in those under 10 years). Dose adjustment is critical to avoid toxicity, particularly in younger children with immature hepatic and renal function. Monitoring for hemolysis and methemoglobinemia is essential, especially in G6PD-deficient patients.¹⁰

Contraindications

Absolute contraindications include known allergy to dapsone, hypersensitivity to sulfonamides, prior agranulocytosis, DHS, or severe anemia. Relative contraindications include G6PD deficiency, methemoglobin reductase deficiency, advanced hepatic disease, cardiac insufficiency, pulmonary disorders, and renal impairment. Caution is required when dapsone is combined with agents that induce methemoglobinemia (e.g., benzocaine, lidocaine). Discontinuation of medications before surgical procedures is recommended to minimize anesthetic risks.

Differential diagnosis

Several conditions can resemble DHS and must be excluded. SJS/TEN presents with widespread skin involvement and mucosal erosions. DRESS shows fever, rash, systemic organ involvement, and marked eosinophilia. Viral hepatitis causes jaundice and abnormal liver function but lacks exfoliative dermatitis. Sepsis produces fever, tachycardia, and hepatitis with positive cultures. Rifampicin hypersensitivity is less common but possible in MDT patients. Autoimmune hepatitis mimics DHS but follows a chronic course with autoantibody positivity.

Advantages and Limitations

This case highlights the importance of early recognition and intervention in promoting recovery. It provides detailed clinical documentation of fever, exfoliative dermatitis, hepatitis, splenomegaly, and anemia. Educationally, it shows that the absence of lymphadenopathy does not exclude DHS. The report contributes to the literature on DHS in young leprosy patients and emphasizes HLA-B 13:01 screening* and steroid tapering strategies. As a single case, findings cannot be generalized. Hematologic evaluation was incomplete, genetic testing was not performed, and follow-up was short. Rifampicin hypersensitivity was not fully excluded, and institutional variability may affect reproducibility.

Preventive strategies

Routine complete blood count (CBC) and liver function monitoring, G6PD screening, and HLA-B 13:01 testing* are recommended. Extended steroid tapering and clinician vigilance for fever, rash, and systemic involvement improve patient safety.

Table 1 summarizes the key hematological and biochemical findings at the time of admission. Values include hemoglobin, liver function tests (AST, ALT, bilirubin, albumin), renal function (creatinine), and viral serologies. The results highlight mild anemia, deranged liver enzymes, hypoalbuminemia, and hyperbilirubinemia, consistent with hepatic involvement in DHS

Table 2 outlines the chronological sequence from initiation of multidrug therapy (MDT) to the onset of symptoms and subsequent management. Key events include the start of MDT, development of fever and rash, progression to exfoliative dermatitis with hepatic involvement, hospital admission, initiation of corticosteroid therapy, and eventual recovery. The timeline highlights the latency period of approximately three weeks between dapsone exposure and the onset of hypersensitivity manifestations.

Table 3 outlines the major conditions evaluated during clinical assessment. Differential diagnoses included Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), viral hepatitis, sepsis with multiorgan dysfunction, rifampicin hypersensitivity, and autoimmune hepatitis. Each condition was considered based on overlapping clinical features such as fever, rash, and hepatic involvement, but was excluded through the absence of mucosal erosions, negative infectious serologies, lack of eosinophilia, or chronic disease markers. The legend highlights the diagnostic reasoning process that supported DHS as the most likely diagnosis.