Rachel Mourot-Cottet

Non-chemotherapy drug-induced neutropenia - an update

ABSTRACT Introduction: To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of ≤0.5 x 109/L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder. Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings. Expert opinion: Idiosyncratic agranulocytosis 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. In this context, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%.

Idiosyncratic drug-induced neutropenia & agranulocytosis

Backgroud: Few data is currently available on neutropenia and agranulocytosis related to drug intake. We report here data on 203 patients with established idiosyncratic drug-induced agranulocytosis, followed up in a referral centre within a university hospital. Patients and methods: Data from 203 patients with idiosyncratic drug-induced agranulocytosis were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis in the Strasbourg University Hospital (Strasbourg, France) Results : The mean age was 61.6 years old (range: 18-95), the gender ratio (F/M) was 1.3. Several comorbidities were present in 63.5%. The most frequent causative drugs were: antibiotics (49.3%), especially s-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors as ticlopidine and acid acetylsalicylic (6.9%). The main primary clinical manifestations during hospitalization included: isolated fever (26.3%); septicaemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%). The mean neutrophil count at nadir was 0.148 x 109/L (range: 0-0.48). All febrile patients were treated with broad-spectrum antibiotics and 107 (52.7%) with hematopoietic growth factors. The mean duration of haematological recovery (neutrophil count ≥1.5 x 109/L) was 7.8 (range: 2-20). This mean duration was reduced to 2.1 days (range: 2-16) (p = 0.057) with hematopoietic growth factors. Outcome was favourable in 91.6% of patients; seventeen died. Thirty-seven patients (18.2%) required intensive care. Conclusions: The present study demonstrated that idiosyncratic drug-induced agranulocytosis is a relative rare events; that antibiotics, antithyroid, neuroleptic and anti-epileptic agents, and platelet aggregation inhibitors are the main incriminated drug classes; that agranulocytosis typically serious, with at least 50% exhibiting severe sepsis and a mortality rate <10%; and that modern management of such disorder may reduce the infection-related mortality.BACKGROUD Few data is currently available on neutropenia and agranulocytosis related to drug intake. We report here data on 203 patients with established idiosyncratic drug-induced agranulocytosis, followed up in a referral centre within a university hospital. PATIENTS AND METHODS Data from 203 patients with idiosyncratic drug-induced agranulocytosis were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis in the Strasbourg University Hospital (Strasbourg, France) RESULTS: : The mean age was 61.6 years old (range: 18-95), the gender ratio (F/M) was 1.3. Several comorbidities were present in 63.5%. The most frequent causative drugs were: antibiotics (49.3%), especially ß-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors as ticlopidine and acid acetylsalicylic (6.9%). The main primary clinical manifestations during hospitalization included: isolated fever (26.3%); septicaemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%). The mean neutrophil count at nadir was 0.148 x 109/L (range: 0-0.48). All febrile patients were treated with broad-spectrum antibiotics and 107 (52.7%) with hematopoietic growth factors. The mean duration of haematological recovery (neutrophil count ≥1.5 x 109/L) was 7.8 (range: 2-20). This mean duration was reduced to 2.1 days (range: 2-16) (p = 0.057) with hematopoietic growth factors. Outcome was favourable in 91.6% of patients; seventeen died. Thirty-seven patients (18.2%) required intensive care. CONCLUSIONS The present study demonstrated that idiosyncratic drug-induced agranulocytosis is a relative rare events; that antibiotics, antithyroid, neuroleptic and anti-epileptic agents, and platelet aggregation inhibitors are the main incriminated drug classes; that agranulocytosis typically serious, with at least 50% exhibiting severe sepsis and a mortality rate <10%; and that modern management of such disorder may reduce the infection-related mortality.

History and Outcome of Febrile Neutropenia Outside the Oncology Setting: A Retrospective Study of 76 Cases Related to Non-Chemotherapy Drugs

Background: Despite major advances in its prevention and treatment, febrile neutropenia remains a most concerning complication of cancer chemotherapy. Outside the oncology setting, however, only few data are currently available on febrile neutropenia related to non-chemotherapy drugs. We report here data on 76 patients with febrile neutropenia related to non-chemotherapy drugs, followed up in a referral center within a university hospital. Patients and methods: Data from 76 patients with idiosyncratic drug-induced febrile neutropenia were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis conducted at the Strasbourg University Hospital (Strasbourg, France). Results: Mean patient age was 52.2 years old (range: 18–93) and gender ratio (F/M) 1.6, with several comorbidities present in 86.8% of patients. The most common causative drugs were: antibiotics (37.4%), antithyroid drugs (17.2%), neuroleptic and anti-epileptic agents (13.1%), non-steroidal anti-inflammatory agents and analgesics (8%), and platelet aggregation inhibitors (8%). Main clinical presentations upon hospitalization included isolated fever (30%), sore throat, acute tonsillitis and sinusitis (18.4%), documented pneumonia (18.4%), septicemia (14.5%), and septic shock (6.6%). Mean neutrophil count at nadir was 0.13 × 10(9)/L (range: 0–0.48). While in hospital, 22 patients (28.9%) worsened clinically and required intensive care unit placement. All patients were promptly treated with broad-spectrum antibiotics, and 45 (59.2%) with hematopoietic growth factors. Mean duration of hematological recovery (neutrophil count ≥1.5 × 10(9)/L) was 7.5 days (range: 2–21), which was reduced to 0.7 days (range: 2–16) (p = 0.089) with hematopoietic growth factors. Outcome was favorable in 89.5% of patients, whereas eight died. Conclusions: Like in oncology and myelosuppressive chemotherapy settings, idiosyncratic febrile neutropenia is typically serious, about 40% of patients exhibiting severe pneumonia, septicemia, and septic shock, with a mortality rate of 10%. Like in febrile, chemotherapy-related neutropenia, modern and timely management (immediate broad spectrum antibiotherapy, hematopoietic growth factors) may reduce infection-related mortality. All practitioners should be aware of this potential side-effect that may even occur in the event of “daily medication” exposure.

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250–1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

Diagnosis and Management of Idiopathic Drug-Induced Severe Neutropenia and Agranulocytosis

In this paper, we report and discuss the diagnosis and management of severe neutropenia and agranulocytosis (neutrophil count of < 0.5 x 109/L) related to drug intake, thus considered as “idiopathic” in case of unpredictable. For practitioners and pharmacists, it is important to keep in mind that almost all classes of drugs have been implicated (“causative”), but for the majority the risk appears to be very small. This rare event (2.4 to 15.4 per million per year), remains a potentially serious adverse event of drugs due to the presence of severe deep tissue infections (e.g., pneumonia), septicaemia, and septic shock in approximately two-thirds of the patients. Recently, several prognostic factors have been identified that may be helpful when identifying frailty patients. Old age (> 65 years), septicaemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1×109/L have been consensually accepted as poor prognostic factors for haematological recovery. In this potentially life-threatening disorder, modern management with broad-spectrum antibiotics and haematopoietic growth factors (particularly G-CSF), is likely to improve the prognosis. Thus, with appropriate management, the mortality rate of idiosyncratic drug-induced agranulocytosis is currently around 5%.

History and outcome of febrile neutropenia related to non-chemotherapy drugs: A retrospective study of the Strasbourg's agranulocytosis cohorte

Despitemajor advances in prevention and treatment, febrile neutropenia (absolute neutrophil count b0.5 × 10(9)/L) remains one of the most concerning complications of cancer chemotherapy, especially in patients receiving myelosuppressive chemotherapy [1]. Outside the context of Oncology, few data are currently available for febrile neutropenia, especially for febrile neutropenia related to non-chemotherapy drugs, called “idiosyncratic agranulocytosis”. In the present paper, we report data on patients with established febrile neutropenia related to non-chemotherapy drugs, followed up in a referral centre within a university hospital. From January 1984 to January 2014 (30 years), 76 patients with febrile neutropenia related to non-chemotherapy drugs, at time of the discovery, were registered (Strasbourgs agranulocytosis cohorte). At the time of the discovery of this drug adverse effect, 8 patients (10.5%) were already hospitalized for one other reason. All patients were Caucasian. Mean age was 52.2 years (range: 18–93); Six patients are aged 85 years or more (7.9%). The female/male ratio was 1.6. Several comorbidities were found in 86.8% of the cases (n= 66), mainly consisting of: thyroid disorders (particularly Graves disease) (22.4%), arterial hypertension (17.1%), cardiac disorders (17.1%), and chronic renal failure (17.1%). A single drugwas documented as “causative” or “likely causative” in all except 12 cases (15.8%), for which two to four drugs were suspected. The main drug families found to be causative were: antibiotics (37.4%), especially β-lactams and cotrimoxazole; antithyroid drugs (17.2%); neuroleptic and anti-epileptic agents (13.1%). At diagnosis, the mean neutrophil count was 0.13 × 10(9)/L (range: 0–0.48). The main discovery circumstance, on the basis of the inclusion criteria used (febrile neutropenia), was fever, as an isolated fever (of unknown origin) in 70 patients (92.1%). Six patients (7.9%) have fever related to pre-existing pneumonias (n = 2), pelvic and abdominal abscess (n=2), andmeningitides (n=2). Themain clinical presentations during hospitalization were: isolated fever (30%); sore throat, acute tonsillitis and sinusitis (18.4%), with one case of maxillar sinus mucormysosis; documented pneumonia (18.4%), with one case of pulmonary aspergillosis and one case of acute respiratory distress syndrome; septicaemia (14.5%); and septic shock (6.6%). Table 1 includes data of the remaining symptomatic patients with documented infection (11.8%). Microbiological documentation was obtained in 21 patients

Idiosyncratic Agranulocytosis in Elderly Patients

Sixty-one patients were identified. One patient presented 2 episodes of IDIA (with 2 different drugs). All patients were Caucasian. The mean and median ages were 84.9 and 82 years (range, 75-95), respectively. The sex-ratio female/male was 2.4. Seventy-four percent of the patients (n=45) presented an underlying disease. Main families of causative drugs were: antibiotics (n=25, 43.8%), especially ß-lactams (n=16) and cotrimoxazole (n=9); antithyroid drugs (n=9, 15.8%); neuroleptic and anti-epileptic agents (n=7, 12.3%); and antiaggregative platelet agents (n=6, 10.5%), especially ticlopidine (n=5). There was only 1 case of self-medication. Discovery circumstances were (n=60): decrease in neutrophil blood counts (n=29, 48.3%); isolated fever (n=22, 36.7%); documented infections (n=8, 13.3%), as acute tonsillitis or pneumonia, with one case of septic shock. Clinical presentations during hospitalization were (n=58): isolated fever (fever of unknown origin) (n=16, 27.6%); documented pneumonia (n=12, 20.7%); septicemia (n=9, 15.5%); septic shock (n=5, 8.6%). The remaining symptomatic patients presented documented infections (n=14, 24.1%), as: acute pyelonephritis (n=4); sore throats and acute tonsillitis (n=4); cutaneous infections (n=1); cholecytitis (n=1); colitis (n=1); infectious spondylitis (n=1); endocarditis (n=1); and fever with deep venous thrombosis (n=1). Two patients (3.4%) remained asymptomatic during the hospitalization. During the hospitalization, 15 patients (25.9%) presented features of severe sepsis, septic shock and/or systemic inflammatory response syndrome (SIRS). Bacteriological documentation (n=54) was obtained in 23 cases (42.6%). At the time of discovery, the mean and median neutrophil counts were 1.62 and 1.5 × 109/L (range, 0.26-6.3). At nadir of the neutrophil decrease, mean and median neutrophil counts were 0.15 and 0.08 × 109/L (range, 0-0.4). Fifty-four percent of patients (n=33) had neutrophil levels of less than 0.1 × 109/L.

Thromboses et syndromes myéloprolifératifs : quoi de neuf dans leur prise en charge ?

Les syndromes myeloproliferatifs (SMP) a chromosome Philadelphie negatif sont les principales hemopathies malignes associees a un risque thrombotique accru. Les strategies pharmacologiques de thromboprevention au cours des SMP sont basees essentiellement sur les antiagregants plaquettaires et/ou le traitement cytoreducteur en fonction de la stratification du risque vasculaire. Quant a la gestion curative d’evenements thromboemboliques chez les patients ayant un SMP, les donnees cliniques en sa faveur restent limitees. Les modalites et la duree du traitement anticoagulant apres une thrombose doivent etre evaluees de facon critique avec une attention particuliere au risque hemorragique associe. Tant pour le traitement en phase aigue que pour la prevention secondaire, les heparines de faible poids moleculaire sont a preferer aux autres anticoagulants. Une prolongation de l’anticoagulation au-dela de trois a six mois est recommandee chez les patients a haut risque en fonction de la maladie hematologique de base et apres evaluation individuelle minutieuse des risques et des benefices. Les nouveaux anticoagulants oraux directs manquent grandement de recul dans cette indication et posent un probleme d’interaction potentielle avec certaines molecules notamment les anti-JAK. Ils sont donc a eviter dans l’etat actuel des connaissances. Le traitement du SMP avec controle periodique et reevaluation de l’efficacite therapeutique reste crucial pour une prevention optimale d’evenement thrombotique.

Comment je traite une péricardite aiguë

Introduction et definitionsLa pericardite se definit par l’association de deux signes parmi les suivants :–douleur thoracique typique (d’installation brutale, soulagee par l’anteflexion, aggravee a l’inspiration profonde, irradiant dans les muscles trapezes) ;–frottement pericardique a l’auscultation (a rechercher en fin d’expiration chez un patient penche en avant) ;–anomalies ECG typiques (sus-decalage concave du ST et sous-decalage du PR a la phase precoce, [...]