Trimethoprim-Sulfomethaxozole (TMP-SMX), a folic acid antagonist, is extensively used for the treatment of pediatric infections. It is clearly known that long term exposure to this drug at high doses is associated with megaloblastic anemia and aplastic anemia(1,2). Antibiotic use is one of the least controlled areas of drug treatment in Turkey where antibiotics are still considered as over-the-counter medications by the majority. Coupled with suboptimal patient education at large, public has easy access to antibiotics through drug stores.

A four-year-old male child presented with a history of anorexia and fatigue for the last several weeks duration. His past medical history was remarkable for an ear infection at six months of age. He was then prescribed TMP-SMX for the treatment of the ear infection. The family noticed that the infant liked the taste of the liquid form of TMP-SMX. The parents continued to purchase the drug for the infant almost in lieu of daily fruit juice replacement. Thus his daily intake of TMP-SMX ranged between 6 to12 mg/kg per day for TMP and 30 to 60 mg/kg per day for SMX since he was 6 months old. The child was neither followed up after the initial ear infection nor admitted to regular health care services because of his parent’s low socio-cultural level. Family history was unremarkable including history of malignancies.

Physical examination revealed a male child with age appropriate growth parameters including weight and height. He displayed mild tachycardia, remark-able pallor, hepatomegaly, and splenomegaly.

Complete blood count revealed severe anemia, normal leukocyte count, and mild thrombocytopenia. Peripheral blood smear revealed lymphoblasts (75% of all white cells) and hypersegmented neutrophils. Biochemical studies revealed low serum levels of vitamin B12 (15 pg/mL) and folic acid (0.5 mg/mL). Bone marrow aspirate revealed L1 morphology by 95%. The diagnosis of pre B cell acute lymphoblastic leukemia (ALL) was confirmed with flow cytometric analysis. TMP-SMX use was discontinued and immediate treatment for ALL was started.

TMP impairs the function of the dihydrofolate reductase enzyme and inhibits the synthesis of folic acid. Folic acid deficiency particularly affects those hematopoietic cells with a rapid turnover. The chronic decreased levels of serum folic acid due to long-term exposure to TMP may cause megaloblastic anemia and thrombocytopenia. The first striking feature of this case is the development of pre B cell ALL on megaloblastic anemia grounds. In 1992, Islam, et al.(3) reported the increased risk of acute and chronic leukemias in patients with long standing megaloblastic anemia. Colagiovanni, et al.(4) emphasized megaloblastic anemia to be a risk factor for leukemia and T cell lymphoma. The exact mechanism for development of leukemia due to prolonged TMP-SMX use is unknown. Aberration factors that control hematopoiesis and specific cytokine responses to chemicals that cause megaloblastic anemia may contribute to the development of leukemia(3,4).

The second striking feature of the case is the occurrence of a series of neglect resulting in the present outcome, including the safety and medical neglect at the family level, safety neglect at the society level that set up the stage for the misuse of a drug, and medical neglect at the physician level by withholding proper patient education.

Orkide Hudaoglu,
Yavuz Tokgöz,
University of Dokuz Eylül,
Faculty of Medicine,
Department of Pediatrics, Izmir,
Turkey.
E-mail: [email protected]