The clinical features of coronavirus disease 2019 (COVID-19) are diverse causing multiple organ failure, cytokine storm, coagulopathy, and still more to be fully characterized. A cluster of methemoglobinemia cases was identified among COVID-19 patients. 1 Methemoglobin cannot bind and release oxygen reversibly and results in decreased oxygen delivery leading to hypoxia. 2 Severe methemoglobinemia can have life-threatening potential and will be further deleterious when compounded by the coexistent cardiopulmonary dysfunction in COVID-19 patients. In this report, red cell exchange (REX) transfusion by apheresis is shown to be an effective treatment of dangerously rising methemoglobinemia that was refractory to other conventional treatments in a patient with severe COVID-19.
A 52-year-old African American male with hypertension, type 2 diabetes mellitus, and morbid obesity (148 kg) was admitted with acute hypoxic respiratory failure. Nasopharyngeal swabs were positive for SARS-CoV-2 by real-time RT-PCR assay. On hospital day 2 (D2), he was placed on mechanical ventilation and norepinephrine was started. On D3, uncontrolled hyperglycemia required insulin drip, and hemodialysis was initiated for acute kidney injury. He completed a trial of hydroxychloroquine and azithromycin treatment over D3 -D7.
Methemoglobinemia was rising rapidly from his baseline of <1% (normal range 0% -1.5%) to 16.8% on D6, and continued to rise to 25.3% on D7 (Fig. 1) . Treatments of methylene blue (MB) and ascorbic acid were given on D7 and D8. MB was administered safely without causing hemolysis after confirming that the patient did not have glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methemoglobinemia, however, was refractory and reached greater than 30% (above the measurable range of the assay) on D9. A venous blood specimen drawn on D9 showed red cells of dark brown color and plasma of dark greenish color, consistent with severe methemoglobinemia and plasma free methemoglobin released from intravascular hemolysis. There was growing concern for the detrimental effects of sharply rising methemoglobinemia in this anemic (hemoglobin 8.3 gm/dL) patient with comorbidities of respiratory failure, shock, and renal failure. To mitigate the adverse effects from worsening methemoglobinemia, a REX by apheresis with replacement of 12 red cell units was performed emergently. The patient was on vasopressors at the time, but hemodynamic status remained stable during REX. Post-REX methemoglobin was reduced to 8.7%. During the following four days, methemoglobinemia had gradually resolved completely and there was no rebound (Fig. 1) , suggesting that the oxidizing events had been discontinued. Intravascular hemolysis was also resolved completely after REX.
Acquired methemoglobinemia is usually caused by exogenous oxidizing chemicals or drugs, 2 and hydroxychloroquine could have precipitated methemoglobinemia in this case. Chloroquine was reported to provoke methemoglobinemia when it was used as malarial prophylaxis. 3 Hydroxychloroquine was administered on D3 -D7, and methemoglobinemia rose rapidly over D6 -D9. Hydroxychloroquine has been used for the patients with rheumatoid arthritis and systemic lupus erythematosus, but methemoglobinemia has not been reported among them. It is probable that certain COVID-19associated conditions and hydroxychloroquine together may confer increased risks for developing methemoglobinemia.
Various modalities of apheresis have been used for treatment of methemoglobinemia of different etiologies. 4 This case is the first report demonstrating that emergent REX could be a potentially lifesaving treatment of refractory severe methemoglobinemia in COVID-19 patients with coexistent compounding comorbidities. This article is protected by copyright. All rights reserved. 