Clinico-Pathologic Characteristics of Patients Experiencing Severe Pyrimethamine Poisoning

Abstract 5162

Pyrimethamine (Pyr) is a folate antagonist with a variety of indications. We report on the inadvertent poisoning of patients with Pyr who underwent bone marrow (BM) biopsy. There were 17 patients (median age 54); the most common presentation was gastrointestinal bleeding and pancytopenia. In January, 2012, hundreds of patients suffering from cardiac conditions were inadvertently poisoned with high dose Pyr at Punjab Institute for Cardiology in Lahore, Pakistan. There were more than 130 fatalities. A batch of isosorbide mononitrate tablets (Isotab, 20 mg) was contaminated with Pyr 50 mg. Patients estimated to have received contaminated drug for 14–21 days (cumulative dosage 2–3 grams). Patients presented with gastrointestinal bleeding, epistaxis, gum bleeding and subconjuntival ecchymosis, 5 with skin darkening, 1 with abdominal pain and vomiting, 4 had infectious complications (2 pneumonias, 2 febrile neutropenias); 1 died due to underlying cardiac disease.

Laboratory analysis demonstrated (mean blood counts at admission): haemoglobin 113 g/L (61–154), white blood cells 2. 55 × 10⁹/L (0. 7–7. 6), platelets 33 × 10⁹/L(4–128). Clinical data provided by Jinnah and Services Hospital, Lahore, Pakistan. BM aspirates reviewed in haematology laboratory, Royal Free Hospital, London. BM samples taken in Pakistan before starting FA, within 2 weeks of stopping Pyr (stained with Romanowsky stain). Blood film, nor data on mean corpuscular volume (MCV) nor BM trephine available. All 17 had normal or hypercellular BM with severe megaloblastosis. Mean myeloid-erythroid ratio 4:1 (14. 7:1–1. 6:1). Severe megaloblastic change, giant metamyelocytes and abnormally lobulated mature granulocytes, 13 of 17 samples were left-shifted, with mild to moderate toxic change in 9. Erythroid lineage was not assessed in 5 due to quality of samples, 13 with marked nuclear:cytoplasmic dysynchrony and moderately severe dysplastic changes: ragged cytoplasm in 13, cytoplasmic bridging in 6, binucleate forms in 6, poor haemoglobinization in 3. Thrombopoiesis adequately assessed in 7, megaloblastic megakaryocytes in 2. High macrophage activity in 1 normocellular BM. Eosinophil count >5% in 6 cases.

Following recognition of the cause, count recovery was prompt following discontinuation of Pyr and admistration of folinic acid (FA), Mean time to recovery of blood counts after FA 3. 89 days (2–5), and in 6 patients returned to normal before FA supplementation. FA started approximately 7 days after BM biopsy (mean time: 6, 5 days (5–10)). Mean duration of admission 10 days (3–28), 14 needed transfusion of blood components.

Notable wide varietry of presentations, symptoms, depth of cytopenias and time to recovery. Part of this may be due to total dose, individual compliance with medication and pre-existing folate stores. In our series absolute dose of Pyr caused megaloblastosis, in patient group not known to be at risk of folate depletion. BM failure and megaloblastosis in absence of identifiable cause should prompt consideration of folate antagonists poisoning. Pyr can cause BM toxicity even as sole agent, independent of co-administration of other folate antagonists. Pyr poisoning, should be suspected in patients with unexplained cytopenias with megaloblastosis. FA therapy results in rapid improvement and should be offered to all patients, initially via the intravenous route.