Brief Case | June 12, 2024 | FREE
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Dapsone-induced methemoglobinemia and hemolytic anemia

A patient being treated for lupus with cutaneous manifestations presented with gradual shortness of breath of about a month's duration.

The patient

A 46-year-old woman with celiac disease and lupus with cutaneous manifestations and inflammatory arthritis who had been on dapsone and hydroxychloroquine for the past few years presented with gradual shortness of breath of about a month's duration. Her symptoms were mostly dyspnea on exertion without any cough, fevers, or other pneumonia symptoms. Upon examination, she had clear lung sounds with 14 to 16 breaths/min and no use of accessory muscles. White blood cells, platelets, electrolytes, and initial chest X-ray were within normal limits. Her liver function tests revealed a mildly elevated bilirubin level of 1.4 mg/dL (reference range, 0.2 to 1.2 mg/dL) with a normal aspartate aminotransferase level of 21 U/L (reference range, 11 to 40 U/L) and a normal alanine aminotransferase level of 18 U/L (reference range, 5 to 46 U/L). COVID-19, influenza, and RSV testing were negative.

Image by Getty Images
Image by Getty Images

The patient was hypoxic on room air and was placed initially on 2 L of supplemental oxygen. An arterial blood gas (ABG) analysis showed SpO2 levels of 141 mm Hg (reference range, 69 to 118 mm Hg) and methemoglobin levels of 12.8% (reference range, <1% to 2%). Her condition progressively worsened and she became pale, requiring up to 15 L of supplemental oxygen even with a PO2 of 288 mm Hg. This rapidly improved with methylene blue and high-dose vitamin C treatment. Further testing revealed haptoglobin levels of less than 10 mg/dL (reference range, 43 to 212 mg/dL), and a peripheral smear showed schistocytes. Her bilirubin level returned to normal by day 3, and she was discharged home without supplemental oxygen. Dapsone was discontinued, and she was doing well at a two-week follow-up.

The diagnosis

The diagnosis is dapsone-induced methemoglobinemia and hemolytic anemia. While dapsone-induced methemoglobinemia has been commonly reported in the literature, with an estimated incidence of up to 20% after oral administration, the concomitant presence of hemolytic anemia is uncommon. Methemoglobinemia is a clinical diagnosis based on history and presenting symptoms, including hypoxemia refractory to supplemental oxygen and the presence of chocolate-colored blood. A history of dapsone intake and hypoxemia out of proportion with clinical findings supports the diagnosis. ABG analysis is routinely used to make a diagnosis of methemoglobinemia. The condition occurs due to the direct hemolytic effect of oxygen free radicals on the red blood cell through dapsone hydroxylamine. This condition can be fatal if not promptly recognized and treated.

Although most cases of dapsone-induced hemolytic anemia occur in patients with G6PD deficiency, there are reports of dapsone-induced hemolytic anemia in transplant recipients with normal G6PD levels. Patients with elevated serum creatinine and lower body weight are at higher risk of this complication. In the setting of solid organ transplant, the incidence of dapsone-induced hemolytic anemia in patients with normal G6PD levels ranges from 23% to 76%. In stem cell recipients, the incidence of hemolysis has been reported to be 87%. Even with treatment, hemolytic anemia can continue for up to two to twelve weeks in such patients.

In addition to ABG, the workup should include investigations to rule out hemolysis, including complete blood count, reticulocyte count, peripheral smear review and measurement of lactate dehydrogenase measurement, liver function, and haptoglobin.


  • Hemolysis workup and methemoglobin levels should be ordered in all patients with suspected dapsone-induced toxicity.
  • Treatment of methemoglobinemia includes removal of the inciting agent, use of the antidote methylene blue, and supplemental oxygen.