A Case of Drug-induced Methemoglobinemia in a Patient with Influenza

DISCUSSION

Methemoglobinemia may develop due to congenital or acquired defects. It usually develops due to one of the following mechanisms: (1) globin chain mutations leading to increased formation of MetHb; (2) deficiency of the MetHb reductase enzyme system; (3) toxic MetHb, in which exposure to substances leads to the formation of excessive MetHb.¹ Patients with anemia are more susceptible to the development of clinical symptoms because of their low functional hemoglobin.² Patients with concurrent hematologic, cardiovascular, or pulmonary disease have symptoms at much lower levels. At levels 20–30%, it causes headaches, exercise intolerance, fatigue, dizziness, mental status changes, and syncope. When the levels of MetHb exceed >50%, it can lead to dysrhythmias, collapse, coma, and death.^2,3

One of the drug-induced acquired causes of MetHb is dapsone, a sulfone drug with potent antibiotic and anti-inflammatory actions. It is commonly used for the treatment of leprosy. Metabolism of dapsone occurs in the liver via the cytochrome P450 pathway, leading to the formation of potential metabolites resulting in MetHb.^2,4,5

Diagnosis of acquired MetHb is by a high index of suspicion in a case of discrepancy between oxygen saturation seen on arterial blood gas study and pulse oximetry, hypoxia that doesn’t improve even after an increased fraction of oxygenation with or without cyanosis in a background of exposure to substances/drugs which can cause oxidation of hemoglobin. Chocolate cyanosis is the hallmark of MetHb, leading to pale skin, lips, and the mucous membranes appearing often more brown than blue in color. Cyanosis occurs usually when the total MetHb level is ≥1.5 gm/dL, but in our index case, there was no cyanosis because the total MetHb was <1.5 gm/dL, even though 16.7% of MetHb was present.^2,6,7

Routine pulse oximetry is imprecise in showing saturation in the presence of MetHb as in our index case because it measures the relative absorbance of 2-wavelengths (i.e., 660 and 940 nm), and MetHb doesn’t absorb light at these 2-wavelengths. Evelyn-Malloy assay is used to detect MetHb levels. Masimo Rad-57, an 8-wavelength pulse oximeter, measures both carboxyhemoglobin and MetHb and, therefore, displays SpCO and SpMet in addition to SpO_2.^3,8,9

Acute toxic MetHb is a medical emergency. The underlying predisposing condition, symptomatology, comorbidities, and the prospect of organ injury from tissue hypoxia will guide treatment. Management usually involves adequate hydration, oxygen therapy, and removing/stopping the offending drugs. Intravenous methylene blue administration at the dose of 1–2 mg/kg is the preferred therapy for severe MetHb with a MetHb level of 20–30% due to its rapid onset of action. It is contraindicated in individuals with glucose-6-phosphate dehydrogenase deficiency because of the inability to produce nicotinamide adenine dinucleotide phosphate, which is required for the formation of leukomethylene blue. Other methods used for management include exchange transfusions, hyperbaric oxygen therapy, and high-dose vitamin C at 4–12 gm/day, which may act as an antioxidant in preventing the transformation of hemoglobin to methemoglobin.^{1-3,6-8,10,11}

The second effect in our patient was ENL, a type 2 lepra reaction, an inflammatory immune complex reaction that occurs before, during, or after the completion of therapy in the lepromatous end of the clinical spectrum. It is usually triggered by immune stimuli like vaccination, Mantoux testing, multidrug therapy initiation, and febrile illness, including upper respiratory tract infections, and in our index case, ENL could have been triggered by H3N2. ENL presents with fever, arthritis, and the development of tender skin nodules that typically appear on previously uninvolved skin. Treatment options to control inflammation include nonsteroidal anti-inflammatory drugs and steroids, as done in our index case.¹²