A Report of Three Girls with Antithyroid Drug-Induced Agranulocytosis; Retrospective Analysis of 18 Cases Aged 15 Years or Younger Reported between 1995 and 2009

Abstract

Agranulocytosis is an extremely serious, although rare, adverse effect of antithyroid drugs (ATDs), including methimazole (MMI) and propylthiouracil (PTU), in children and adolescents. There are few reports about the characteristics of ATD-induced agranulocytosis in Japanese children and adolescents. This report presents the cases of three girls with ATD-induced agranulocytosis and a retrospective analysis of 18 patients with ATD-induced agranulocytosis, whose cases had been referred to the drug manufacturer, Chugai Pharmaceutical Co., Ltd. Our 3 patients, ranging in age from 12 to 14 yr, developed ATD-induced agranulocytosis between the 15th and 57th day of ATD treatment for hyperthyroidism. Fever and sore throat were the earliest symptoms of agranulocytosis. The patients were rescued by ceasing ATD therapy and administering antibiotics, potassium iodide, glucocorticoid, immunoglobulin and granulocyte colony-stimulating factor (G-CSF). We retrospectively analyzed 18 cases of ATD-induced agranulocytosis treated with MMI in 16 cases and PTU in 2 cases. Twelve patients were treated with 20–45 mg/d MMI. Agranulocytosis developed between the 15th and 1,344th day of therapy. In conclusion, considering the risk of ATD-induced agranulocytosis, we recommend low-dose MMI therapy for treatment of Graves’ disease.

Methimazole Induced Total Myeloid Aplasia with Delayed Recovery Despite Granulocyte Colony Stimulating Factor (G-CSF): Marrow Progenitor Recovery Kinetics

“…The lag time to response to G-CSF suggests degree of depletion of committed myeloid progenitors and indeed pluripotent stem cells. Consistent with this, prior observations have shown that growth factors are not effective in cases with severely low ANC (\100) [15]. Bone marrow recovery from agranulocytosis after G-CSF treatment can be delayed when pretreatment bone marrow M:E ratio is \0.5 (mean, 9.8 days) compared to patients who had a M:E ratio C0.5 (mean, 2.2 days) [16].…”

Associations of HLA genotypes with antithyroid drug‐induced agranulocytosis: A systematic review and meta‐analysis of pharmacogenomics studies

“…Although cross‐reactivity among ATD is common, PTU was used as alternative treatment for patients with CMZ/MMI‐induced agranulocytosis . Our sensitivity analysis excluding PTU showed the pooled ORs by risk of HLA‐B*27:05 and HLA‐B*38:02 were much increased in cases excluding PTU‐induced agranulocytosis, suggesting HLA‐B*27:05 and HLA‐B*38:02 may be more specific to CMZ/MMI‐induced agranulocytosis.…”

“…Data were pooled separately by study design using random-effects model; the inverse variance technique was used for pooling of measures of effects Data were pooled separately by study design using random-effects model; the inverse variance technique was used for pooling of measures of effects agranulocytosis 36. Our sensitivity analysis excluding PTU showed thepooled ORs by risk of HLA-B*27:05 and HLA-B*38:02 were much increased in cases excluding PTU-induced agranulocytosis, suggesting HLA-B*27:05 and HLA-B*38:02 may be more specific to CMZ/MMI-induced agranulocytosis.…”

Patient Knowledge of Antithyroid Drug-Induced Agranulocytosis

“…Review of the literature of reported cases of agranulocytosis between 1999 and 2013 identified 80 cases where the presenting symptoms were described [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Fever (93.8%), sore throat (68.7%) and chills (21.2%) were the commonest presenting symptoms.…”