Q J Med 2001; 94: 423-428
© 2001 Association of Physicians
Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis
1 From the Departments of Internal Medicine, 2 Internal Medicine and Nutrition and 3 Onco-Hematology, University of Strasbourg, Strasbourg, France
Received 30 March 2001 and in revised form 25 May 2001
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Summary |
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Drug-induced agranulocytosis (DIA) is often caused by antithyroid drugs. We retrospectively studied the use of granulocyte colony-stimulating factor (G-CSF) therapy in antithyroid-DIA. Data for 20 patients (10 treated with G-CSF) with antithyroid-DIA (neutrophil count <0.5x109/l) were extracted from a cohort study of DIA patients (n=110). G-CSF (300 µg/day subcutaneously) was used where the neutrophil count was <0.1x109/l, or the patient was aged >70 years, or there were severe features of infection or underlying disease. Mean patient age was 62 years (range 34–87); sex ratio (M/F) was 0.05. Carbimazole (n=19) and benzylthiouracile (n=1) were the causative drugs, at mean doses of 30 mg/day (range 20–60) and 100 mg/day (range 50–150), respectively, for a mean of 37 days (range 31–90). Antithyroid drugs were prescribed for Graves' disease (n=8), thyrotoxicosis related to amiodarone intake (n=6) and multinodular goitre (n=6). Clinical features included isolated fever (n=7), pneumonia (n=5), septicaemia or septic shock (n=5) and acute tonsillitis (n=3). Mean neutrophil count was 0.07±0.1x109/l. No patient died. Mean durations of haematological recovery, antibiotic therapy and hospitalization were significantly reduced with G-CSF: 6.8±4 days vs. 11.6±5; 7.5±3.8 days vs. 12±4.5; and 7.3±4.8 days vs. 13±6.1, respectively (all p<0.05). G-CSF induced flu-like symptoms in 30% of patients, but reduced overall costs.
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Introduction |
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Drug-induced agranulocytosis (DIA) is a rare disorder (annual incidence: 0.8–3.3 cases/year/million)1,2 with a poor prognosis (mortality rate: 6–20%).3,4 Antithyroid drugs (e.g. methimazole, carbimazole and benzylthiouracil) are frequently associated with DIA.5,6 In this setting, haematopoietic growth factors (e.g. granulocyte colony-stimulating factor, G-CSF) are widely administered, although their efficacy remains controversial.7
We evaluated the use of G-CSF in antithyroid-DIA in patients from our cohort study, particularly in DIA caused by carbimazole and benzylthiouracil, agents that are commonly administered in France.
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Methods |
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Patients
Between January 1985 and December 2000, all DIA cases among hospitalized patients at the Hopitaux Universitaires de Strasbourg (a tertiary referral center) were recorded in a cohort study (partial data have been published7). Patients were recruited from the Departments of Onco-Hematology, Internal Medicine, Geriatrics, Rheumatology and Digestive Surgery.
All data were obtained from patient files, including medical history (particularly thyroid disease), clinical status, relevant biochemical and bacteriological data, blood cell count and marrow examination (when available). Treatment, especially use of hematopoietic growth factors and antibiotherapy, time to recovery (>1.5x109/l neutrophils in blood count) and outcome (mortality and morbidity) were also recorded.
Criteria for entry and exclusion from the study
All patients included in this study had confirmed DIA. Agranulocytosis was defined according to the criteria of the International Agranulocytosis and Aplastic Anemia Study (IAAAS) as <0.5x 109/l neutrophils (on two blood cell counts), presence during hospitalization of fever and/or clinical infection and/or signs of septic shock (chills and sweat, collapses, confusion).8 DIA was defined using criteria reported by Benichou et al. as the onset of agranulocytosis during treatment or within 7 days in cases of previous administration of the same drug, and complete recovery after drug withdrawal (no clinical symptoms and neutrophil count of >1.5x109/l one month after drug withdrawal).9 Inclusion criteria are listed in Table 1
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Procedure in cases of DIA
When agranulocytosis was suspected, a member of our medical team was contacted within 24 h for confirmation. If the diagnosis was established, it was reported to the Centre de Pharmacovigilance de Strasbourg, and the patient was followed in the Department of Onco-Hematology or Internal Medicine. In cases of DIA, any suspected drug was immediately stopped, and parenteral antibiotics were introduced (combination of beta-lactam and aminoside) in cases of sepsis. Since 1993 (F. Maloisel, personal communication), G-CSF was also initiated, according to our criteria of poor prognosis (adapted from reference 3, manuscript in preparation). These included neutrophil count<0.1x109/l, age >70 years, severe clinical features of infection (e.g. collapsus, septicaemia, extensive pneumonia) or evidence of an underlying disease (e.g. chronic cardiac or respiratory failure, renal failure, diabetes mellitus). G-CSF (filgrastime, Amgen/Roche, or lénograstime, Aventis) was used at a fixed dose of 300 µg/day subcutaneously. Haematopoietic growth factors were started within 48 h of the diagnosis of DIA, and were continued until the neutrophil count exceeded at least 1.5x109/l.
Statistical analysis
To investigate the usefulness of hematopoietic growth factors, the patients were retrospectively classified into two groups with regard to the use of G-CSF. The main comparison criteria were outcome and mortality rate, time to haematological recovery, and tolerance. The duration of antibiotherapy and hospitalization were also recorded, and a cost study (based on hospitalization, antibiotics and G-CSF costs) was performed. The statistical analysis was done using Statview software. Data were analysed using the 
2 test, the Mann-Whitney test and the t test for paired data. Statistical significance was set at p<0.05.
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Results |
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Between January 1985 and December 2000, 110 patients were diagnosed with DIA (data published in part6,7,10). Twelve patients were excluded from the cohort, due to development of thrombocytopenic purpura (n=1), malignant Hodgkin's lymphoma (n=1) and myelodysplastic syndrome (n=1) or incomplete data (n=9).
Twenty patients had antithyroid-DIA and are analysed in the present work (preliminary data were previously published11). These patients were recruited between March 1991 and December 2000 (5 patients were recruited before 1993, when G-CSF was not used in poor-prognosis DIA). Myelograms were available from 13 patients, particularly for all the patients treated with G-CSF. Results were non-specific, but excluded underlying haematological disease (e.g. myelodysplastic syndrome). Bone-marrow findings showed myeloid hypocellularity with apparent cessation of myeloid precursor maturation in eight patients, or the presence of ‘immature’ bone marrow with increased myeloid precursors in five.
Clinical characteristics
The main characteristics of patients are listed in Table 2. All patients were White Europeans. The median age was 62 years (range 37–87). The ratio of men to women was 1:19. An underlying disease (chronic cardiac or respiratory failure, renal failure, or diabetes mellitus) was found in 30% of cases. All patients had thyrotoxicosis, with a mean TSH of 0.1 mU/l (normal 0.15–4.5) and free T4 19.2 pg/ml (normal 9.5–18) as related to different disorders including Grave's disease (n=8, 40%), thyrotoxicosis related to amiodarone intake (n=6, 30%) and multinodular goitre (n=6, 30%).
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A single drug was causative in all cases: carbimazole in 19 patients and benzylthiouracil in one. The mean doses of carbimazole and benzylthiouracil were 30±12 mg/day (range 20–60) and 100±37 mg/day (range 50–150), respectively. Mean duration of drug intake was 37 days (range 31–90). Seven patients ingested additional drugs for a long time—mean two drugs (range 1–4).
Clinical features at diagnosis included isolated fever (n=12, 60%), pneumonia and acute tonsillitis (n=2, 10%) and sepsis (n=1) (Table 2
). Identification of five cases of DIA (25%) was fortuitous (discovered on routine blood cell count). The spectrum of clinical features during hospitalization included isolated fever (n=7, 35%), pneumonia (n=5, 25%), acute tonsillitis (n=3, 15%) with necrosis in one case, and septicemia or septic shock (n=5, 25%).
A pathogen was isolated from blood cultures of five patients (25%): Streptococcus pneumoniae (n=2), Staphylococcus aureus (n=2) and Candida albicans (n=1).
Of these 20 patients, G-CSF was administered to 10 and their characteristics were compared to the remaining 10 patients who did not receive growth factors. Their clinical features were well balanced, but there was a significant difference in the initial blood parameters between the two groups. The mean neutrophil count was 0.12x109/l (±0.107) for the group not given G-CSF vs. 0.03x109/l (±0.18) for the group with G-CSF (p=0.04) (Table 2).
Response to G-CSF
Clinical and biological features are summarized in Table 3. The ten patients who were treated with G-CSF received a dose of 300 µg/day subcutaneously for a mean duration of 6.1 days (range: 4–15).
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Outcome was favourable in 100% of subjects (no patient died). Complications, e.g. aggravation of sepsis (acute tonsillitis and pneumonia) and/or occurrence of septicaemia were equal, at 5 in each group. Mean duration for haematological recovery (neutrophil count >1.5x109/l) of all patients was 9±4.8 days (range 4–18): 6.8±4 days for patients treated with G-CSF (range 4–16) vs. 11.6±5 days for patients without G-CSF (range 5–18) (p<0.046) (Table 3
). The mean duration for neutrophil count >0.5x109/l was also significantly reduced with G-CSF: 6.1 days vs. 10.2 days (p=0.041). Mean duration of antibiotic therapy (7.5±3.8 days vs. 12±4.5 days) and hospitalization (7.3±4.8 days vs. 13±6.1) also favoured the group that received G-CSF (p=0.038). Compliance with G-CSF therapy was good, and no severe adverse events were observed. Mild flu-like syndromes (fever <38 °C, chills, arthralgia, myalgia) were reported in 30% of cases (at therapy initiation).
Based on the mean durations of hospitalization, antibiotherapy and G-CSF therapy in each group, a rapid cost evaluation suggested that the use of G-CSF saved 
$2000/patient (mean costs per day: hospitalization $400, antibiotics $40, and G-CSF therapy $80).
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Discussion |
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The definition of DIA remains controversial.14 Some investigators require all the elements of the historical definition: neutrophil count <0.5x109/l, health impairment and severe mucositis,15 or a neutropenia <0.1x109/l. Our patient diagnoses were in agreement with the consensual definition of DIA proposed by the IAAAS and by Benichou et al.8,9 They had a neutrophil count <0.5x109/l (100%), clinical features of sepsis (100%) and documented bacterial pathogen (25%) (Table 2
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Our study is consistent with the features of antithyroid-DIA that appear in the literature.12,13 Our data are consistent with its severity in some patients, with life-threatening infections such as pneumonia and acute tonsillitis (rarely necrotic tonsillitis) (40%) and septicemia or septic shock (25%) (Table 2).
Our data suggest that despite the severity of the initial clinical picture (underlying disease in 30% of cases associated with a sepsis in 70% of cases and a mean neutrophil count of 0.07±0.1x109/l), an appropriate management of DIA, especially with the use of broad-spectrum antibiotherapy and G-CSF, may improve the prognosis. All patients clinically recovered, and a quicker haematological recovery was observed in the G-CSF group (6.8±4 days vs. 11.6±5 days).
All our patients had confirmed DIA, and at diagnosis their clinical characteristics were well balanced between the two groups (with or without G-CSF) even though this was a non-randomized study.
Significant improvements were observed in association with G-CSF therapy for all the comparison criteria. The mean duration for haematological recovery was significantly reduced by 4.8 days, even though the initial neutrophil count significantly favoured the group without G-CSF (0.03x109/l vs. 0.12x109/l, p<0.001). The duration of antibiotic therapy and of hospitalization were also reduced with G-CSF treatment (-4.5 days, p=0.041 and -2.5 days, p=0.038). However, clinical outcome was the same in the two groups. G-CSF therapy induced only minor morbidity (flu-like syndrome in 25% of cases) and reduced the overall cost of managing this disorder (by $2000/patient). A shorter hospitalization probably also reduces the likelihood of nosocomial infections.
We would like to emphasize that all these results were observed in patients with poor prognosis and severe DIA, as previously described.3 Among the first 55 patients of our cohort, duration of haematological recovery, hospitalization and antibiotherapy with or without G-CSF were not statistically different, but the majority of the patients did not have the poor prognosis criteria.7
However, the present results are consistent with those of recent larger studies of G-CSF therapy in DIA that included antithyroid-DIA.16,17 In a case-control study of 70 patients, Sprikkelman et al. demonstrated that G-CSF and granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced the recovery of neutrophils count (from 4 to 7 days), especially in patients with a neutrophil count <0.1x109/l.16 Haematopoietic growth factors also reduced the incidence of fatal complications, with a mortality rate of 5%. The same conclusion was obtained in a review of 118 patients (all published case reports treated with G-CSF or GM-CSF).17 The mean time to neutrophil recovery was 7.7±5.1 days with growth factors (neutrophil count <0.1x109/l) vs. 10±8 days. The mortality rate was also reduced: 4.2% with G-CSF or GM-CSF vs. 16%. Against this, the only available prospective randomized study did not confirm the benefit of G-CSF in 24 patients with antithyroid-DIA.18 But in our opinion, this result may be related to the use of inappropriate G-CSF doses (100–200 µg/day) and perhaps also to the absence of a well-defined target population.
Although our results, in accordance with others,16,17 strongly support the effect of G-CSF therapy in the management of severe DIA, they must be interpreted with caution. The major concern is that our study was not randomized. Two patients of the group without G-CSF had several indicators of poor prognosis, but were not treated with G-CSF because it was not available yet (inclusion before 1990). Other concerns are: (i) it was a one-centre study with a limited sample size (rare disorder); and (ii) we included only patients with specific characteristics (hospitalized with severe agranulocytosis and/or several concomitant diseases). However, enough data are reported in the literature to consider a placebo study unethical.16,17 In our opinion, future studies must focus on determining the appropriate dose of G-CSF and selecting the subset of patients that will benefit from G-CSF therapy in drug-induced agranulocytosis.
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Acknowledgments |
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We are indebted to Professors Marc Imler, Jean-Marie Brogard, Daniel Storck, Francis Kuntzmann, Jean-Louis Kuntz, Jean Sibilia, Daniel Jaeck, P. Wolff and Christian Meyer, and to Drs George Kaltenbach, Catherine Martin, Nathalie Neyrolles and Jean-Christophe Weber, who participated in this study. We are also indebted to Dr Margaret E. Black, who kindly edited the English of the text.
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Notes |
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Address correspondence to Dr E. Andrès, Service de Médecine Interne de la Clinique Médicale B, CHRU de Strasbourg, Hôpital Civil, 1 Place de l'Hôpital, 67 091 Strasbourg Cedex, France. e-mail: emmanuel.andres{at}chru\|[hyphen]\|strasbourg.fr
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Sheng WH, Hung CC, Chen YC, Fang CT, Hsieh SM, Chang SC, et al. Antithyroid drug-induced agranulocytosis complicated lfe threatening infections. Q J Med 1999; 92:455–61.
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