Dapsone-Induced Methemoglobinemia

Introduction: Methemoglobinemia is a state in which hemoglobin-associated iron is oxidized to Fe3+, resulting in allosteric changes to hemoglobin that inhibit oxygen release to peripheral tissues. It is often secondary to oxidizing substances like benzocaine, nitrates, and dapsone, a sulfa derived antibiotic that can be used for pneumocystis jiroveci (PCP) prophylaxis. Methemoglobinemia presents with nonspecific headache, weakness, and fatigue along with unexplained hypoxemia and cyanosis that do not improve with supplemental oxygen. The saturation gap, or the difference between a depressed pulse oximetry reading (SpO2) and a normal oxygen saturation (SaO2) on arterial blood gas (ABG), is characteristic. This is an artifact of pulse oximetry technology, which measures SpO2 by calculating the difference between absorption of distinct light wavelengths for hemoglobin and oxy-hemoglobin. As oxyhemoglobin falls, SpO2 drops, plateauing around 85%. In contrast, ABG measures oxygen partial pressure directly to estimate SaO2, neither of which change in methemoglobinemia. Case Description: An 84-year-old woman presented with rapidly progressive glomerulonephritis and, after kidney biopsy showed diffuse cellular crescents, was diagnosed with PR-3 ANCA vasculitis. She had no pulmonary manifestations. She was treated with pulse-dose steroids, cyclophosphamide, and plasma exchange. G6PD level was normal and she was given dapsone for PCP prophylaxis. Despite kidney recovery and decreasing PR-3 ANCA titer, she developed worsening hypoxia. Hemoptysis and cough were absent. Chest X-ray was clear and chest computed tomography (CT) showed no evidence of pneumonia or diffuse alveolar hemorrhage. VQ scan excluded pulmonary embolism. Echocardiogram with bubble study was normal. A trial of furosemide did not improve oxygenation. Pulse oximeter measured oxygen saturation of 88% with no improvement after administration of 6 liters oxygen by nasal cannula. ABG demonstrated oxygen partial pressure of 100 mmHg. Serum methemoglobin level was elevated to 7.6%. With withdrawal of dapsone therapy and addition of high dose oral ascorbic acid, hypoxia resolved. Discussion: Glucocorticoids are the basis of ANCA vasculitis treatment, causing iatrogenic immunocompromise and necessitating PCP prophylaxis. While hypoxemia has many potential culprits in syndromes that include pulmonary manifestations, dapsone use should prompt consideration of methemoglobinemia.