Dapsone is a Potent Cause for Iatrogenic Methemoglobinemia: A Case Report for Iatrogenic Methemoglobinemia:

Methemoglobinemia is a blood disorder in which blood methemoglobin levels are >1% leading to defective O 2 supply to body tissues. It leads to a shift of the oxygen dissociation curve to the left. We present a case involving a young boy who was taking dapsone for 3 months, developed dyspnea and peripheral cyanosis, was diagnosed as methemoglobinemia, and was given antidote therapy. Patients with respiratory symptoms and cyanosis but normal pO 2 in arterial blood gases and saturation gap >5% have a high index of suspicion for methemoglobinemia.


Introduction
Dapsone was synthesized about 100 years ago, but its use remained limited to leprosy and malaria due to its toxic effects. Recently, since the advent of HIV, it is widely used to treat Toxoplasma gondii encephalitis and Pneumocystis carinii pneumonia in acquired immune deficiency syndrome (AIDS).
Its dermatological uses include treatment against dermatitis herpetiformis and linear immunoglobulin A (IgA) [1]. However, important but rare adverse effects of Dapsone include doserelated hemolysis and methemoglobinemia. Other side effects are psychosis, hypersensitivity syndrome, agranulocytosis, aplastic anemia, peripheral neuropathy, sulfone syndrome. Cyanosis in a patient with the use of dapsone has a high index of suspicion for the diagnosis of methemoglobinemia if saturation gap > 5% [2] as in the case of our patient who was diagnosed and treated with IV methylene blue in time.

Case Report
A 17-year-old male presented to the emergency department with gradually progressive shortness of breath and bluish discoloration of lips, hands, nails and feet. No history of fever, cough, or hemoptysis. History revealed that he was diagnosed with Behcet's disease and was using dapsone 100 mg per day and steroids for 3 months.General physical examination was normal except for peripheral cyanosis. He was vitally stable, but saturation was 77% at room air with bilateral equal air entry and no added sounds on auscultation of the chest. Saturation did not ECG and chest X-ray was normal. HRCT chest done, which showed normal lung fields.Echocardiography was normal, with a 60% ejection fraction. Methemoglobin levels were 34%. He was hence, diagnosed as Dapsone induced Methemoglobinemia and given methylene blue 1.5mg/kg (100mg) IV stat dose, then repeated daily for 2 more days till methemoglobin levels fell less than 10%.
Dapsone was discontinued.

Discussion
Methemoglobin is different from hemoglobin as one or more of its four iron atoms are in ferric (Fe 3+ ) rather than ferrous (Fe 2+ ) state and incapable of binding oxygen [3]. Methemoglobinemia is a blood disorder where the MetHb level is>1%of the Hb level in the blood, thus unable to release oxygen effectively to body tissues leading to the hypoxic condition [4]. Methemoglobin is naturally formed in the body at a rate of 3% per day in response to oxidative stress but is neutralized by 2 pathways to convert methemoglobin to hemoglobin, which is cytochrome b5-MetHb reductase pathway using NAD and nicotinamide adenine dinucleotide phosphate (NADPH)-MetHb reductase, using NADPH [5]. if not treated immediately [8]. In the presence of a high index of suspicion, Methemoglobinemia can be diagnosed via a "saturation gap" between the saturation recorded from the pulse oximeter as compared to the reported saturation in the arterial blood gas in setups with limited resources.  [9] provided that G-6PD levels are normal and there is adequate production of NADPH to reduce methylene blue to leukomethylene blue. "Blue cures blue but be cautious." One should be cautious in the administration of methylene blue in G-6PD deficiency patients; the reason being G-6PD deficiency can cause dapsone-induced hemolytic anemia but not methemoglobinemia unless concurrent oxidizing drugs are given [10].

Conclusion
Adverse effects associated with dapsone therapy should be kept in mind while prescribing it, and if a patient using dapsone develops any adverse signs and symptoms like dyspnea and hypoxemia, they should be suspected of dapsone induced methemoglobinemia.
And methylene blue is the antidote against methemoglobinemia, provided that G6PD levels in the body are normal.