A 6-year-old boy was admitted for rituximab infusion as treatment for refractory chronic immune thrombocytopenia (ITP). He was diagnosed to have immune thrombocytopenia three years ago, and has been on treatment with multiple courses of steroids, azathioprine, cyclosporine, eltrombopag and dapsone to which thrombocytopenia remained refractory. At the time of initiation of weekly rituximab, he was on dapsone (2 mg/kg/day) and cyclosporine (3 mg/kg/day), and platelet count was maintained around 5-10 × 109/L with occasional episodes of epistaxis and gum bleeding. Normal G6PD level was ensured prior to starting dapsone. He was hemodynamically stable with normal oxygen saturation (SpO2) in room air during the first dose of rituximab. In view of having received prolonged courses of steroids, he was started on PCP prophylaxis with TMP/SMX (5 mg/kg/day of trimethoprim) thrice a week. During second week of admission, while monitoring for rituximab infusion, his SpO2 was found to be 88% in room air. Child was comfortable with normal respiratory rate and had no cough, running nose, dyspnea, exertional intolerance, dark colored urine or cyanosis, and systemic examination was unremarkable. The possibility of methemoglobinemia as well as viral interstitial lung disease was considered; arterial blood gas analysis showed methemoglobin level of 14.9% (normal <2%) and arterial oxygen saturation (PaO2) of 90 mmHg. Dapsone and TMP/SMX were stopped, and he was followed up clinically with SpO2 monitoring once in 3-4 days. Hemoglobin remained constant at 11 g/dL and there was no evidence of hemolysis. Repeat methemoglobin level after two weeks was 0.3% with PaO2 of 109 mmHg.

Methemoglobinemia following prophylactic doses of TMP/SMX is extremely rare [1,2]. Although dapsone is a well-known cause of methemoglobinemia, it did not cause any symptoms in our patient for over 6 months. The other drugs being administered (cyclosporine and rituximab) are not known causes of methemoglobinemia in usual doses. The addition of cotrimoxazole might have caused a ‘dose-effect’ with dapsone resulting in methemoglobinemia. Methemoglobinemia following combination of dapsone with TMP/SMX combination has been reported in HIV patients receiving these drugs in therapeutic dosage for PCP [3]. Since TMP/SMX is used very commonly in pediatric oncology and immunodeficiencies, the early recognition of this complication by SPO2 monitoring may be warranted.

3. Medina　I, Mills J, Leoung G, Hopewell PC, Lee B, Modin G, et al. Oral therapy for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim- dapsone. N Engl J Med. 1990;323:776-82.