RESUMO
BACKGROUND: Infection may lead to agranulocytosis due to bone marrow suppression. However, a rare case with infection presented with morphological features of acute myeloid leukemia (AML). METHODS: We report a case of extreme agranulocytosis due to severe infection mimicking acute myeloid leukemia. The case was definitively diagnosed by subsequent morphology, flow cytometry, and bone marrow biopsy, and subsequent successful anti-infective treatment confirmed the diagnosis. CONCLUSIONS: To date, no case of a patient diagnosed with severe infection mimicking AML has been reported. The case emphasizes the importance of an integrated diagnostic work-up, especially careful clinical observation and differential diagnosis.
Assuntos
Agranulocitose , Leucemia Mieloide Aguda , Humanos , Medula Óssea/patologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Diagnóstico Diferencial , Citometria de Fluxo , Agranulocitose/diagnóstico , Agranulocitose/patologiaAssuntos
Agranulocitose/complicações , Leucemia de Células T/complicações , Receptores de Antígenos de Linfócitos T gama-delta/análise , Linfócitos T/patologia , Adulto , Agranulocitose/genética , Agranulocitose/patologia , Feminino , Humanos , Leucemia de Células T/genética , Leucemia de Células T/patologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Adulto JovemRESUMO
BACKGROUND: Thionamide-induced agranulocytosis (TIA), namely antithyroid drug (ATD)-induced agranulocytosis, is one of the most feared adverse effect of ATDs. It is defined as a granulocyte count of less than 0.5 × 109/L after ATD administration. Several studies reported that TIA is associated with human leukocyte antigen (HLA) and nearby genes. Our previous study found that the susceptibility genes of TIA are similar in north China and European populations. METHODS: We evaluated the associations of 23 candidate single nucleotide polymorphisms (SNPs) in 37 patients with TIA and 254 patients with Graves' disease (GD) as controls by iPLEX MassARRAY system. RESULTS: Five SNPs in the MHC class I polypeptide-related sequence A(MICA) genes [rs4349859 (p = 1.43E-7); rs145575084 (p = 5.79E-6); rs116135464 (p = 3.70E-5); rs148015908 (p = 3.79E-5) and rs189600525 (p = 2.15E-4)] were found to be significantly associated with TIA after Bonferroni correction. After combining with previous data of rs4349859 and HLA-B*27:05, the haplotype analysis showed that patients carrying P-A-C-A-T-T-A haplotype have a higher risk of TIA (p = 9.76E-7; OR = 14.85, 95% CI 3.63-60.77). CONCLUSION: Our findings suggest that five high linked SNPs of MICA gene are significantly associated with susceptibility to TIA.
Assuntos
Agranulocitose/patologia , Antitireóideos/efeitos adversos , Predisposição Genética para Doença , Doença de Graves/tratamento farmacológico , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo de Nucleotídeo Único , Adulto , Agranulocitose/induzido quimicamente , Agranulocitose/epidemiologia , Agranulocitose/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , PrognósticoRESUMO
Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10-7, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10-3, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10-3), Taiwanese (P = 1.1 × 10-3), and European populations (P = 5.2 × 10-4). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (Pmeta = 1.2 × 10-9, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
Assuntos
Agranulocitose/genética , Antitireóideos/uso terapêutico , Doença de Graves/tratamento farmacológico , Cadeias HLA-DRB1/genética , Agranulocitose/induzido quimicamente , Agranulocitose/patologia , Alelos , Antitireóideos/efeitos adversos , Feminino , Frequência do Gene , Estudos de Associação Genética , Doença de Graves/complicações , Doença de Graves/genética , Doença de Graves/patologia , Haplótipos/genética , Humanos , Japão/epidemiologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Fatores de RiscoRESUMO
INTRODUCTION: Neutropenia and agranulocytosis are rare side effects of deferiprone (DFP) in patients treated for iron overload. Unfortunately, no study directly addressed special risks in countries with a background of ethnic neutropenia, such as Oman. AIM: The aim of this study was to report the incidence of neutropenia in Omani children with ß-thalassemia treated with different iron chelators. METHODS/DESIGN: This was a retrospective study that included 179 Omani pediatric patients. For patients who developed neutropenia, demographic data, iron-chelating agent, clinical presentation, management, and outcome were recorded. Detailed clinical, laboratory±radiologic information was added for patients with agranulocytosis. RESULTS: Neutropenia was encountered in 43.6% of patients: severe neutropenia in 10 patients, moderate in 29, and mild in 69 patients. Severe and moderate neutropenia had similar incidence among DFP-exposed and DFP-naive patients (P=0.515 and 0.421, respectively), while mild neutropenia was common among DFP-naive patients (P=0.0001). A higher incidence of DFP-related agranulocytosis (4.1%) was noted compared with previous reports, but none had a fatal outcome. CONCLUSIONS: In a community with ethnic neutropenia, mild to moderate neutropenia is common. Higher incidence of severe neutropenia and agranulocytosis mandates careful monitoring and rational modification of iron-chelating agents to avoid life-threatening complications.
Assuntos
Agranulocitose/epidemiologia , Etnicidade/estatística & dados numéricos , Quelantes de Ferro/efeitos adversos , Neutropenia/epidemiologia , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Agranulocitose/etiologia , Agranulocitose/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neutropenia/etiologia , Neutropenia/patologia , Omã/epidemiologia , Prognóstico , Estudos Retrospectivos , Adulto Jovem , Talassemia beta/patologiaRESUMO
OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.
Assuntos
Agranulocitose/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Acidente Nuclear de Chernobyl , Neutropenia Febril/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Exposição à Radiação/efeitos adversos , Agranulocitose/etiologia , Agranulocitose/mortalidade , Agranulocitose/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Criança , Esquema de Medicação , Neutropenia Febril/etiologia , Neutropenia Febril/mortalidade , Neutropenia Febril/patologia , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Granulócitos/patologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Contagem de Leucócitos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Doses de Radiação , Indução de Remissão , Análise de SobrevidaRESUMO
OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.
Assuntos
Agranulocitose/induzido quimicamente , Alemtuzumab/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Listeriose/induzido quimicamente , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Agranulocitose/mortalidade , Agranulocitose/patologia , Alemtuzumab/administração & dosagem , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/patologia , Evolução Fatal , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Listeriose/microbiologia , Listeriose/mortalidade , Listeriose/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Pneumonia/microbiologia , Pneumonia/mortalidade , Pneumonia/patologiaRESUMO
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.
Assuntos
Agranulocitose/genética , Clozapina/efeitos adversos , Neutropenia/genética , Esquizofrenia/tratamento farmacológico , Agranulocitose/induzido quimicamente , Agranulocitose/epidemiologia , Agranulocitose/patologia , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Estudos de Associação Genética , Genótipo , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Humanos , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/patologia , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genéticaRESUMO
Since 1893, eosinopenia is a biological test to help a diagnosis of bacterial infection. Several publications have confirmed this hypothesis, particularly in the intensive care, pneumology and pediatric units. The value of this marker has been identified in vascular cerebral diseases and coronary bypass. Its contribution seems as relevant as procalcitonin, without extra cost. The diagnostic performance of this test was reinforced by a composite score (CIBLE score) that may improve its value in daily routine. Finally, monitoring eosinopenia appears to be a reliable mortality marker.
Assuntos
Agranulocitose/diagnóstico , Eosinófilos/patologia , Hematologia/tendências , Agranulocitose/etiologia , Agranulocitose/patologia , Infecções Bacterianas/sangue , Infecções Bacterianas/complicações , Infecções Bacterianas/diagnóstico , Hematologia/métodos , Humanos , Contagem de Leucócitos , PrognósticoRESUMO
Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.
Assuntos
Agranulocitose/epidemiologia , Agranulocitose/genética , Clozapina/efeitos adversos , Esquizofrenia/epidemiologia , Adulto , Agranulocitose/induzido quimicamente , Agranulocitose/patologia , Alelos , Clozapina/administração & dosagem , Estudos de Coortes , Análise Custo-Benefício , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genéticaAssuntos
Clozapina/efeitos adversos , Colite/induzido quimicamente , Estado Terminal , Infecções por Citomegalovirus/induzido quimicamente , Agranulocitose/patologia , Antipsicóticos/efeitos adversos , Colite/complicações , Colite/diagnóstico , Colite/virologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Neutropenia/patologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologiaAssuntos
Agranulocitose/etiologia , Antifúngicos/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Voriconazol/efeitos adversos , Idoso , Agranulocitose/sangue , Agranulocitose/diagnóstico , Agranulocitose/patologia , Síndrome de Hipersensibilidade a Medicamentos/sangue , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/patologia , Feminino , Humanos , Meropeném/uso terapêutico , Aspergilose Pulmonar/tratamento farmacológico , Pele/patologiaRESUMO
BACKGROUND: Acute leukemia is the most common pediatric hematological malignancy. Bloodstream infections (BSIs) are severe complications in these patients during chemotherapy. This study aimed to explore the clinical presentation and etiology of BSI, as well as the common sites of infection, and to provide a basis for the rational regarding antibiotic use. METHODS: We performed a retrospective chart review of all pediatric patients who had acute leukemia accompanied by a BSI in our hospital from December 2011 to September 2015. All patients were selected based on clinical presentation and had to have at least one positive blood culture for inclusion. The basic clinical characteristics, blood culture results, and antimicrobial susceptibilities were analyzed. RESULTS: All 231 patients had a fever; of them, 12 patients continued to have a fever. Twenty-five patients had nonremitting (NR) leukemia, and 206 patients achieved complete remission (CR). Differences in the duration of fever between the NR and CR groups were significant (9.6 ± 7.9 vs. 5.1 ± 3.8 days, P= 0.016). One hundred and eighty patients had agranulocytosis. Differences in fever duration between the agranulocytosis and nonagranulocytosis groups were significant (6.2 ± 5.1 vs. 4.1 ± 2.6 days, P= 0.001). The other sites of infection in these 231 patients were the lung, mouth, digestive tract, and rectum. Blood culture comprised 2635 samples. There were 619 samples, which were positive. Of the 619 positive blood culture samples, 59.9% had Gram-negative bacteria, 39.3% had Gram-positive bacteria, and 0.8% had fungus. The primary pathogens were Pseudomonas aeruginosa, Enterobactercloacae, Escherichia coli, and Klebsiella pneumoniae. Of these 231 patients, 217 patients were cured. The effective treatment ratio was 94%. CONCLUSIONS: Gram-negative bacteria were the main pathogenic bacteria in patients with acute leukemia in our center. NR primary illness, agranulocytosis, and drug-resistant pathogenic bacteria were all risk factors for poor prognosis.
Assuntos
Bacteriemia/etiologia , Bacteriemia/patologia , Leucemia Mieloide Aguda/patologia , Doença Aguda , Agranulocitose/etiologia , Agranulocitose/patologia , Criança , Pré-Escolar , Feminino , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/patogenicidade , Humanos , Lactente , Leucemia Mieloide Aguda/etiologia , Masculino , Estudos RetrospectivosRESUMO
Good's syndrome is an immunodeficiency disease involving thymoma accompanied by hypogammaglobulinemia. We encountered a case of Good's syndrome accompanied by agranulocytosis that followed a rapid clinical course. A 72-year-old man visited our hospital with a two-week history of a sore throat. Candida albicans was detected in the pharynx, and hypogammaglobulinemia was detected in addition to granulocytopenia. The patient subsequently developed septic shock and followed a rapid clinical course which ended in death. Good's syndrome with agranulocytosis was diagnosed at autopsy. Good's syndrome accompanied by agranulocytosis can follow a rapid clinical course and some cases remain asymptomatic until old age. Its prompt treatment is crucial.
Assuntos
Agamaglobulinemia/imunologia , Agranulocitose/patologia , Síndromes de Imunodeficiência/patologia , Timoma/patologia , Neoplasias do Timo/patologia , Idoso , Agranulocitose/complicações , Agranulocitose/tratamento farmacológico , Agranulocitose/imunologia , Autopsia , Evolução Fatal , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , Masculino , Faringite/etiologia , Síndrome , Timoma/complicações , Timoma/tratamento farmacológico , Timoma/imunologia , Neoplasias do Timo/complicações , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/imunologiaRESUMO
A 29-year-old male with transfusion-dependent ß-thalassemia major (ß-TM), splenectomized and on chelation therapy with deferiprone (DFP or L1) due to heart and liver hemosiderosis, presented with high fever and agranulocytosis. Deferiprone was discontinued and a broad spectrum antibiotic therapy was started intravenously. The patient remained febrile and showed no recovery of neutrophil count even after the initiation of granulocyte colony-stimulation factor (G-CSF). After 12 days at the hospital, he developed respiratory failure and was transferred to the intensive care unit (ICU) where he developed multi-organ failure and died 3 days later. To investigate the mechanism of agranulocytosis, bone marrow mononuclear cells of a healthy volunteer were plated on culture dishes, with or without the patient's serum. The observation of colony forming units of progenitor cells in dishes that contained the patient's serum, provided inconclusive explanation of the possible mechanism of DFP-induced agranulocytosis. This is a case of fatal agranulocytosis developing in a patient being treated with DFP, a well recognized but rare complication of this drug. Further studies are required in order to elucidate the possible pathogenic mechanism of agranulocytosis due to DFP and to provide clear guidelines in order to best care for the patient.
Assuntos
Agranulocitose/induzido quimicamente , Piridonas/efeitos adversos , Talassemia beta/complicações , Adulto , Agranulocitose/diagnóstico , Agranulocitose/patologia , Células da Medula Óssea/patologia , Exame de Medula Óssea , Terapia por Quelação/efeitos adversos , Deferiprona , Evolução Fatal , Humanos , Leucócitos Mononucleares/patologia , Masculino , Piridonas/uso terapêutico , Células-Tronco/patologia , Talassemia beta/tratamento farmacológicoRESUMO
INTRODUCTION: While in most countries warfarin is the preferred anti-vitamin K, fluindione, a molecule with a prolonged half-life remains largely prescribed in France. Some of its side effects, including immuno-allergic complications, remain poorly understood. CASE REPORT: A 77-year-old woman presented with a febrile severe neutropenia of immunoallergic mechanism with a favourable outcome associated with fluindione, introduced 25 days earlier for the treatment of atrial fibrillation. CONCLUSION: This rare side effect is a reminder of the importance of biological monitoring in the first weeks following the introduction of fluindione and key diagnostic elements and therapeutic aspects of iatrogenic agranulocytosis.
Assuntos
Agranulocitose/induzido quimicamente , Anticoagulantes/efeitos adversos , Fenindiona/análogos & derivados , Idoso , Agranulocitose/patologia , Neutropenia Febril Induzida por Quimioterapia/patologia , Hipersensibilidade a Drogas/patologia , Feminino , França , Humanos , Fenindiona/efeitos adversosRESUMO
BACKGROUND: Drug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis. Previous studies of levamisole, suggest that the human leukocyte antigen (HLA)-B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased. METHODS: We performed a case-control study using a genotyping assay and novel gene chip to test the association between cocaine-associated agranulocytosis (CAA) and HLA-B27 and to identify pharmacokinetic and pharmacodynamic gene variants associated with the phenotype. RESULTS: Fifty-one CAA cases were identified through a provincial physician reporting system between 2008 and 2011. We examined eight of these cases and 26 matched controls. Genotyping revealed a significant association between HLA-B27 and CAA (odds ratio [OR] 9.2, 95% confidence interval [CI], 1.54-54.6). We also observed a similar association with the HLA-B27 tag single nucleotide polymorphism rs4349859 (OR 9.2, 95% CI 1.5-54.6) and rs13202464 (OR 6.7, 95% CI 1.1-41). Further associations were identified with variants in the ARBCC12 (OR 10.0, 95% CI 2.7-36.8) and CYP11A1 (OR 7.4, 95% CI 2.1-26.6) genes, while a novel protective association was observed with variants in the ARDB1 gene (OR 0.06, 95% CI 0.007-0.46). CONCLUSIONS: We confirmed the association of HLA-B27 with CAA and identified additional susceptibility variants. Health care providers should inform people who are identified as having CAA that it is genetically determined and can recur with continued cocaine use. The severity of infections and subsequent hospitalization, and the risk of recurrence may prompt health-promoting behaviour changes of the affected individuals. These genetic associations warrant the attention of public health and knowledge translation efforts to highlight the implications for susceptibility to this severe adverse drug event.