“…The oxidative process can also be accomplished by cytochrome P450 (CYP); in fact, this may be the clue to why some drugs that cause neutropenia or agranulocytosis can also cause liver toxicity. Immune mechanisms also seem to have a role in pathogenesis, as previously documented with positive lymphocyte transformation tests [ 16 ]. Circulating antibodies against differentiated granulocytes may be responsible for propylthiouracil-induced agranulocytosis, rendering this process immune mediated [ 17 ].…”
Section: Pathophysiologymentioning
confidence: 83%
“…These antibodies, which can be anti-neutrophil cytoplasmic antibodies (ANCA), react against specific granules inside the neutrophils when they migrate to the cell membrane, inducing apoptosis. These antibodies can also react with myeloid progenitor cells [ 17 ] and induce opsonization of neutrophils, mediated by the complement system [ 16 ]. Fig.…”
Section: Pathophysiologymentioning
confidence: 99%
“…Sepsis should be suspected, particularly if fever, chills and prostration present suddenly. Despite the typical presentation of fever, 15% of patients can be asymptomatic [ 16 ], although they can become symptomatic shortly after diagnosis [ 12 ].…”
Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/μl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.
“…The oxidative process can also be accomplished by cytochrome P450 (CYP); in fact, this may be the clue to why some drugs that cause neutropenia or agranulocytosis can also cause liver toxicity. Immune mechanisms also seem to have a role in pathogenesis, as previously documented with positive lymphocyte transformation tests [ 16 ]. Circulating antibodies against differentiated granulocytes may be responsible for propylthiouracil-induced agranulocytosis, rendering this process immune mediated [ 17 ].…”
Section: Pathophysiologymentioning
confidence: 83%
“…These antibodies, which can be anti-neutrophil cytoplasmic antibodies (ANCA), react against specific granules inside the neutrophils when they migrate to the cell membrane, inducing apoptosis. These antibodies can also react with myeloid progenitor cells [ 17 ] and induce opsonization of neutrophils, mediated by the complement system [ 16 ]. Fig.…”
Section: Pathophysiologymentioning
confidence: 99%
“…Sepsis should be suspected, particularly if fever, chills and prostration present suddenly. Despite the typical presentation of fever, 15% of patients can be asymptomatic [ 16 ], although they can become symptomatic shortly after diagnosis [ 12 ].…”
Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/μl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.
“…The results of the present study seem to support this recommendation. The blood neutrophil count at every medical visit when prescribing ATDs has recently demonstrated to correctly diagnose 64% and 94% of patients with agranulocytosis without or with minimum infection symptoms when prescribing ATDs [14,26]. However, the lack of impact on mortality and morbidity leads to a debate regarding blood count monitoring [7,8].…”
Background: The most important series devoted to antithyroid drug-induced severe neutropenia and agranulocytosis are Japanese studies, almost specifically in relation to the intake of methimazole. The clinical data of 30 Caucasian patients followed up for antithyroid drug-induced neutropenia at a third-level hospital are reported. Methods: The data of 30 patients with idiosyncratic antithyroid drug-induced neutropenia and agranulocytosis from a cohort study on drug-induced neutropenia and agranulocytosis conducted at the University Hospital of Strasbourg (France) were retrospectively reviewed. Results: The mean patient age was 61.7 years old (range: 20–87), and the gender ratio (F/M) was 4. Several comorbidities were reported in 23 patients (76.7%), with the mean Charlson comorbidity index of 1. The causative drugs were carbimazole and benzylthiouracil, in 28 (93.3%) and 2 cases, respectively, prescribed primarily for multi-hetero-nodular goiter or thyroid nodule to 18 patients (60%). Sore throat and acute tonsillitis (40%), isolated fever (20%), septicemia (13.3%), documented pneumonia (6.7%), and septic shock (6.7%) were the main clinical features upon admission. The mean neutrophil count at nadir was 0.02 and 0 × 109/L (range: 0–0.3). Regarding the patients’ hospital course: 13 cases (43.3%) worsened during hospitalization, severe sepsis was found in 26.7%, systemic inflammatory response syndrome—in 13.3%, and septic shock—in 3.3% of the cases, respectively. Broad-spectrum antibiotics were indicated for all the patients, and 21 (73.3%) of them received hematopoietic growth factors. Hematological recovery (neutrophil count ≥ 1.5 × 109/L) was seen at 8.3 days (range: 2–24), but faster in those receiving hematopoietic growth factors (4.9 days, p = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. Conclusions: Antithyroid drug-induced neutropenia represents a serious complication resulting from the rates of severe infections especially in those cases severe neutropenia. In this setting, an established procedure for the management of patients seems useful or even indispensable in view of potential mortality.
“…However, for drugs such as antithyroid medications, ticlopidine, clozapine, sulfasalazine, trimethoprim-sulfamethoxazole, and dipyrone, the risk may be higher [2,3]. For example, for antithyroid drugs, a risk of 3 per 10,000 users has been reported [45,46]. For ticlopidine, the risk is more than 100-fold higher [2,3].…”
Introduction: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases. Materials and methods: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: “drug-induced neutropenia”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis”. We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor. Results: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1–2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3–4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF). Conclusion: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.
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