Olivier Keller

Drug-Induced Agranulocytosis in Elderly Patients: Diagnosis and Management of Life-Threatening Infections and Septic Shock

In this paper, we discuss the diagnosis and management of life-threatening infections including septic shock, in elderly patients presenting with acute drug-induced neutropenia (neutrophil count of 65 years), septicemia or septic shock, metabolic disorders such as renal failure and a neutrophil count below 0.1 × 109/L. In this potentially life-threatening disorder, modern management with broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF), is likely to improve the prognosis, even in elderly patients.

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.

Clinical Articularities of Drug-induced Agranulocytosis or Severe Neutropenia inElderly Patients

Agranulocytosis is a life-threatening disorder in any age and also in the elderly subjects who are receiving on the average a larger number of drugs than younger subjects. This disorder frequently occurs as an adverse reaction to drugs, particularly to antibiotics, antiplatelet agents, anti-thyroid drugs, neuroleptics or anti-epileptic agents and nonsteroidal anti-inflammatory agents. Although patients experiencing drug-induced agranulocytosis may initially be asymptomatic, the severity of the neutropenia usually translates into the onset of severe sepsis that requires intravenous broad-spectrum anti-biotherapy. In this setting, hematopoietic growth factors have been shown to shorten the duration of neutropenia. Thus with appropriate management, the mortality rate of idiosyncratic druginduced agranulocytosis is now of 5% to 10%. Today, drug-induced agranulocytosis still remains a rare event with an annual incidence from 3 to 12 cases per million of people. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management.

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.

Et pan ! On l’a pas toujours dans l’os… !

ObservationMonsieur X, âge de 66 ans, d’origine caucasienne, a ete hospitalise pour des douleurs du flanc droit associees a des vomissements et un syndrome febrile. L’interrogatoire retrouvait comme principaux antecedents une hypertension arterielle essentielle traitee par une association amiloride-hydrochlorothiazide, une goutte sous allopurinol, ainsi qu’une arthrose sous chondroitine sulfate. Il rapportait par ailleurs plusieurs episodes d’infections urinaires febriles par [...]

Une fausse jaunisse noire

ObservationM. X est âge de 64 ans et d’origine marocaine. Il vit en France depuis 20 ans et est maintenant a la retraite apres avoir travaille dans le bâtiment. Il est ancien fumeur mais n’a pas d’autres antecedents medicaux. Il est revenu d’un voyage de 5 mois dans ses montagnes natales et consulte aux urgences le meme jour, pousse par sa famille. Il se plaint d’une « chaleur » qui va et vient, de sueurs nocturnes, d’une toux seche, d’arthralgies et de douleurs abdominales [...]

Traitement du myélome multiple : actualités et perspectives

Longtemps traite par l’association classique alkylants-corticoides, le myelome multiple a connu ces dernieres annees des avancees physiopathologiques reelles, rapides et concretes ayant debouche sur l’arrivee en masse de molecules innovantes qui ont transforme le pronostic de la maladie. Il s’agit essentiellement des inhibiteurs du proteasome et des imides qui constituent a cote de l’autogreffe la pierre angulaire de toutes les lignes therapeutiques actuelles du myelome multiple. Par ailleurs, le diagnostic et les indications therapeutiques du myelome sont de plus en plus codifies et font l’objet de recommandations constamment revisitees et actualisees, des recommandations qui plaident malgre cette codification grandissante en faveur d’une approche personnalisee en fonction d’une cartographie pronostique de plus en plus moderne prenant en consideration a la fois les donnees cliniques, biologiques, immunologiques et cytogenetiques des patients. Dans cet article, nous passons en revue ces principales avancees et leurs implications pratiques dans la prise en charge quotidienne du myelome multiple.

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.