Case Presentation: 35 year old African American Female with history of HIV of 16 years duration, not on antiretroviral therapy, was admitted to the hospital with shortness of breath, generalized weakness, and poor appetite of 2 week duration. She had been admitted to the hospital a month ago for candidal esophagitis and discharged on dapsone 100 mg daily for Pneumocystis Carinii prophylaxis (due to sulfa allergy). She was initially treated with oral prednisone, clindamycin and primaquine for presumed PCP pneumonia despite no radiographic evidence on chest X ray or CT scan. During the course of admission, she continued to have low pulse oximetry readings (88-92% on 4 Liters Oxygen delivered by oxymask) despite oxygen therapy and developed perioral cyanosis. An arterial blood gas (ABG) was performed which revealed normal partial pressure of oxygen (198 mmHg) with elevated methemoglobin levels 24.9%. Methemoglobinemia was diagnosed and Dapsone, Primaquine and Clindamycin were stopped. She was given intravenous methylene blue which improved her symptoms along with pulse oximetry readings and methemoglobin levels gradually reduced over 3 days. She was discharged on atovaquone and ascorbic acid with plans to initiate antiretroviral therapy as outpatient.
Discussion: Methemoglobinemia occurs when normal ferrous state of iron is oxidized to ferric state causing left shifting of oxygen dissociation curve resulting in functional anemia and cellular hypoxia. This clinically presents as cyanosis and headaches but it can also cause altered mental status, seizure and death. Among the various causes of acquired methemoglobinemia, dapsone is one of the most common precipitating agents. Dapsone undergoes N-hydroxylation by various P450 enzymes in liver to N-hydroxy dapsone which results in dose related methemoglobinemia. As Methemoglobin has characteristic light absorption spectrum, it causes falsely low oxygen saturation on pulse oximetry although partial pressure of oxygen is normal. Definitive diagnosis can be established by co-oximetry or elevated methemoglobin levels on arterial blood gas analysis. Methylene blue is the treatment of choice due to its rapid onset of action. When methylene blue is not available or in patients with G6PD deficiency, ascorbic acid is a safe alternative. Due to longer half life of dapsone (about 30 hours), methemoglobinemia due to dapsone is prolonged with worse outcomes compared to other toxic causes. It often requires serial monitoring of methemoglobin levels and sometimes retreatment with methylene blue. In cases where dapsone needs to be continually used, cimetidine has been shown to decrease methemoglobinemia by inhibition of cytochrome P450 system without affecting therapeutic efficacy of dapsone.
Conclusions: Dapsone is a common cause of methemoglobinemia which can cause impaired oxygen delivery to tissues resulting in cellular hypoxia. It should be suspected in the clinical setting of cyanosis, low pulse oximetry readings and normal partial pressure of oxygen on ABG and can be diagnosed by co-oximetry and elevated methemoglobin levels. Methylene blue is the preferred treatment in symptomatic methemoglobinemia except in cases of G6PD deficiency when ascorbic acid is preferred. Although rare, physicians should be aware of this potential complication as immediate recognition and timely treatment can be life saving.