LAUSR

We recently read the article by Torabi et al published in your journal. Diagnosing methemoglobinemia in the setting of transplantation is challenging, as mostly the transplant patients are on multiple drugs and it is difficult to pinpoint a culprit drug. We aim to reinforce the importance of awareness of adverse effects with various drugs used during transplantation that may lead to methemoglobinemia. Methemoglobinemia is a well-known entity but is challenging if encountered in transplant setting. Dapsone is considered as second-line alternative for Pneumocystis carinii pneumonia (PCP) prophylaxis and is used if either the patient is allergic or not responding to bactrim. Long half-life thereby allowing intermittent dosing and low cost are the 2 major benefits of using dapsone. However, hemolytic anemia, leucopenia, and methemoglobinemia are serious complications of dapsone. Pathologically, N-hydroxylated and hydroxylamine metabolites of dapsone are known to cause methemoglobinemia. Due to high prevalence of dapsone-induced methemoglobinemia (up to 20%), the awareness about this entity is of extreme importance. In an National Health Service (NHS) funded study, Mitsides et al found methemoglobinemia in 12 of 26 transplant recipients on dapsone. Theoretically, renal transplant recipients should have highest prevalence of methemoglobinemia because dapsone is excreted by kidneys. Individuals with methemoglobin percentage >30% have higher chances of requiring ventilatory support. With nonspecific symptoms of breathlessness, cyanosis, and tachycardia, methemoglobinemia can be easily confused with many other conditions such as febrile neutropenia, anemia, pneumonia, and graft-versus-host disease. Esbenshade et al did an excellent study on dapsone-related methemoglobinemia in 167 pediatric oncology patients. Methemoglobinemia was noted in 32 (19.8%) patients. They found a significant observation of 73% risk reduction in methemoglobin percentage with dosing 20% below the target dose of 2 mg/kg/d. Gender, body mass index, age, and cytochrome b5 reductase enzyme activity status (CYB5RA) were not associated with increased risk to develop methemoglobinemia. Apart from dapsone, other agents like cyclophosphamide/ifosfamide (used as preconditioning agent) has also been recently reported to cause methemoglobinemia. The mechanism proposed was 4-thioifosfamide, which is a deactivated ifosfamide metabolite, reacts with glutathione, thereby depleting the cell antioxidant stores. Plotkin et al also reported 2 cases with solid organ transplant developing dapsone-induced methemoglobinemia; both were managed with methylene blue and subsequently started on monthly aerosolized pentamidine therapy for PCP prophylaxis. Note that inhaled pentamidine is 5 to 7 times costlier than dapsone ($125/month vs $17/month). There are various other alternatives for PCP prophylaxis, for example, atovaquone, azithromycin, and so on. Although dapsone is probably more cost-effective than the others, none of the studies have compared them with regard to cost of hospitalization or drug-induced adverse events. Considering the side effect profile, few centers have started measuring MHb levels routinely. Methemoglobinemia is an important entity due to its excellent outcome if treated promptly. Before commencing dapsone, patients should be counseled about risk of methemoglobinemia and must be checked for Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Regular monitoring of methemoglobin percentage is recommended while using dapsone.