RESUMO
INTRODUCTION: The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development. AIM: To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors. METHODS: The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA. RESULTS: Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects. CONCLUSION: Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population.
Assuntos
Anticorpos/sangue , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Fator VIII/administração & dosagem , Hemofilia A/imunologia , Humanos , Masculino , IrmãosRESUMO
BACKGROUND: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand factor (VWF) replacement therapy. There are little data on the use of prophylaxis in VWD, and none have been applied in a prospective, treatment escalation design. OBJECTIVE: Evaluate the effect of escalating dose prophylaxis in severe VWD. METHODS: Patients eligible for enrollment in this prospective study included those with type 1 VWD with VW factor activity-ristocetin cofactor ratio ≤ 20% and unresponsive to desmopressin, patients with type 2 VWD not responsive to desmopressin and all subjects with type 2B and type 3 VWD. Entry criteria were strictly defined, as were therapy escalation parameters and clinical data collection. RESULTS: Eleven subjects completed the study. Six had type 2A, and five had type 3 VWD. Six patients presented with epistaxis, three with GI bleeding, and two with joint bleeding. Seven had dose escalation above the first level. Among the 10 subjects with evaluable bleeding log data, use of prophylaxis decreased the median annualized bleeding rate from 25 to 6.1 (95% confidence interval of the rate difference: -51.6 to -1.7), and the median annualized bleeding rate was even lower (4.0; 95% confidence interval: -57.5 to -5.3) when the subjects reached their final dosing level. CONCLUSION: This is the first prospective study to demonstrate that prophylaxis with VW factor concentrates is highly effective in reducing mucosal and joint bleeding rates in clinically severe VWD.
Assuntos
Hemorragia/prevenção & controle , Doenças de von Willebrand/complicações , Fator de von Willebrand/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Ensaios Clínicos como Assunto , Desamino Arginina Vasopressina/uso terapêutico , Esquema de Medicação , Fator VIII/uso terapêutico , Feminino , Hemartrose/etiologia , Hemartrose/prevenção & controle , Hemorragia/etiologia , Hemorragia/terapia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Menorragia/etiologia , Menorragia/prevenção & controle , Estudos Multicêntricos como Assunto , Hemorragia Pós-Operatória/prevenção & controle , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Doenças de von Willebrand/tratamento farmacológicoRESUMO
Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Tolerância Imunológica , Isoanticorpos/imunologia , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Criança , Pré-Escolar , Fator VIII/genética , Fator VIII/uso terapêutico , Hemofilia A/complicações , Hemofilia A/diagnóstico , Humanos , Lactente , Isoanticorpos/sangue , Mutação , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
The high cost of clotting factor concentrate (CFC) used to treat haemophilia and von Willebrand disease (VWD) attracts health plans' attention for cost management strategies such as disease management programmes (DMPs). In 2004, Indiana's high risk insurance health plan, the Indiana Comprehensive Health Insurance Association, in partnership with the Indiana Hemophilia and Thrombosis Center developed and implemented a DMP for beneficiaries with bleeding disorders. This report evaluates the effectiveness of the DMP 5 years post implementation, with specific emphasis on the cost of CFC and other medical expenditures by severity of disease. A pre/post analysis was used. The main evaluation measures were total cost, total outpatient CFC IU dispensed and adjusted total outpatient CFC cost. Summary statistics and mean and median plots were calculated. Overall, 1000 non-parametric bootstrap replicates were created and percentile confidence limits for 95% confidence intervals (CI) are reported. Mean emergency department (ED) visits and mean and median duration of hospitalizations are also reported. The DMP was associated with a significant decrease in mean annualized total cost including decreased CFC utilization and cost in most years in the overall group, and specifically in patients with severe haemophilia. Patients with mild and moderate haemophilia contributed little to overall programme expenditures. This specialty health care provider-administered DMP exemplifies the success of targeted interventions developed and implemented through a health care facility expert in the disease state to curb the cost of specialty pharmaceuticals in conditions when their expenditures represent a significant portion of total annual costs of care.
Assuntos
Gerenciamento Clínico , Custos de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/estatística & dados numéricos , Hemofilia A/tratamento farmacológico , Hemofilia A/economia , Adulto , Fatores de Coagulação Sanguínea/economia , Fatores de Coagulação Sanguínea/uso terapêutico , Serviço Hospitalar de Emergência/economia , Feminino , Hospitalização/economia , Humanos , Masculino , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII/genética , Haplótipos/genética , Hemofilia A/genética , Autoanticorpos/sangue , Estudos de Coortes , Análise Mutacional de DNA , Fator VIII/antagonistas & inibidores , Predisposição Genética para Doença , Hemofilia A/imunologia , Humanos , MutaçãoRESUMO
Antibodies directed towards non-neutralizing epitopes on the factor VIII protein (FVIII) may be detected in patients with haemophilia A. We evaluated the prevalence of non-neutralizing antibodies, in 201 inhibitor-negative brother pairs with severe haemophilia A, enrolled in the Malmö International Brother Study and the Haemophilia Inhibitor Genetics Study. To evaluate binding specificity of the antibodies, ELISA plates were coated with two recombinant full-length (FL) FVIII-products and one recombinant B-domain-deleted (BDD) product. Seventy-nine patients (39.3%) had a history of positive inhibitor titre measured by Bethesda assay, and FVIII antibodies were detected in 20 of them (25.3%). Additional 23 samples from subjects without a history of FVIII inhibitors were ELISA-positive corresponding to a frequency of non-neutralizing antibodies of 18.9%. The antibody response towards the different FVIII products was heterogenous, and was raised not only towards the non-functional B-domain but also towards both FL-rFVIII and BDD-rFVIII. In patients considered successfully treated with immune tolerance induction, 25.4% had remaining FVIII antibodies. The number of families with an antibody response in all siblings was increased when the total antibody response was taken into account, further supporting the concept of a genetic predisposition of the immune response. Further studies and careful monitoring over time are required to appreciate the immune response on the risk of inhibitor development or recurrence in the future.
Assuntos
Autoanticorpos/sangue , Fator VIII/imunologia , Hemofilia A/imunologia , Irmãos , Adolescente , Adulto , Idoso , Autoanticorpos/imunologia , Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Humanos , Tolerância Imunológica/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around 'classic' 'proximal' promoter polymorphisms: -592, -819 and -1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.
Assuntos
Síndrome da Imunodeficiência Adquirida/genética , HIV-1 , Haplótipos/genética , Interleucina-10/genética , Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/virologia , Animais , Estudos de Coortes , Progressão da Doença , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras GenéticasRESUMO
The screening of common genetic polymorphisms among candidate genes for AIDS pathology in HIV exposed cohort populations has led to the description of 20 AIDS restriction genes (ARGs), variants that affect susceptibility to HIV infection or to AIDS progression. The combination of high-throughput genotyping platforms and the recent HapMap annotation of some 3 million human SNP variants has been developed for and applied to gene discovery in complex and multi-factorial diseases. Here, we explore novel computational approaches to ARG discovery which consider interacting analytical models, various genetic influences, and SNP-haplotype/LD structure in AIDS cohort populations to determine if these ARGs could have been discovered using an unbiased genome-wide association approach. The procedures were evaluated by tracking the performance of haplotypes and SNPs within ARG regions to detect genetic association in the same AIDS cohort populations in which the ARGs were originally discovered. The methodology captures the signals of multiple non-independent AIDS-genetic association tests of different disease stages and uses association signal strength (odds ratio or relative hazard), statistical significance (p-values), gene influence, internal replication, and haplotype structure together as a multi-facetted approach to identifying important genetic associations within a deluge of genotyping/test data. The complementary approaches perform rather well and predict the detection of a variety of undiscovered ARGs that affect different stages of HIV/AIDS pathogenesis using genome-wide association analyses.
Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Biologia Computacional/métodos , Predisposição Genética para Doença , Genoma Humano , HIV-1 , Estudos de Coortes , Interpretação Estatística de Dados , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Subject reports of efficacy of treatment of haemophilia-related joint bleeding are by definition subjective, yet are often the primary outcome in studies comparing therapies. Verbal descriptors such as effective, partially effective, poorly effective, not effective are treated as dichotomous or categorical variables in analyses, lowering the statistical power relative to that which might be achieved with a continuous variable. The aims of this study were to examine reports of pain recorded on a 100-mm visual analogue scale (VAS) during the course of joint bleeding; determine whether pain varied by treatment period among pairs reporting discordant outcomes on a verbal scale (one product effective, the other not effective); test whether the two products under study were equivalent with respect to VAS scores; and evaluate their relationship to verbal reports of efficacy. Data from the international, prospective, randomized, crossover FEIBA NovoSeven Comparative study of two bypassing agents used for treatment of 96 bleeding episodes in 48 participants were examined. VAS scores were associated with verbal descriptors of efficacy at every time point, and were equivalent between treatment periods. There were differences in mean scores at time points at which participants rated one treatment effective, the other not effective. As a continuous variable, the VAS score may have more power than a dichotomous variable and when used with verbal descriptions of efficacy can improve the overall accuracy of assessment. This report highlights an important consideration in the selection of outcome measurement that can be generalized to other haemophilia treatment research.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Hemartrose/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Modelos Estatísticos , Adolescente , Adulto , Criança , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Medição da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
A study of major joint outcomes, specifically range of motion and synovitis, was conducted with data from a subset of adolescents enrolled in the prospective Hemophilia Growth and Development Study (HGDS). Clinical observations were carried out over a 7-year period from 1989 to 1996. A secondary aim was to gain insight into factors that might influence decisions regarding maintaining or discontinuing prophylaxis during early adulthood. Twenty-nine participants (median age 17.4 at entry) were included. Median follow-up was 7 years (range: 4.8-7.7). Range of motion (ROM) and synovitis in six major joints (knees, elbows and ankles), were evaluated by physical examination every 6-12 months. At the baseline observation, 73.6% of joints showed no ROM abnormalities or synovitis, and all joints were normal in 11 patients. Of the 11 participants, 54.5% developed abnormalities and 28.1% of normal joints at baseline became abnormal during the follow-up. Ankles were the most severely affected and had persistent progression during late adolescence and adulthood. Elbows and knees did not show progression after the first few years of the follow-up. The progression of haemophilic arthropathy in adolescents and young adults varies from individual to individual and also in the site of affected joints. In view of this, the decision regarding discontinuation of prophylaxis in patients with haemophilia should be individualized.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Hemofilia A/complicações , Artropatias/etiologia , Sinovite/psicologia , Adolescente , Adulto , Criança , Humanos , Artropatias/prevenção & controle , Estudos Longitudinais , Estudos Prospectivos , Amplitude de Movimento Articular/fisiologia , Sinovite/prevenção & controle , Resultado do TratamentoRESUMO
Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.
Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Crescimento , Fatores Etários , Envelhecimento/fisiologia , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/fisiopatologia , Antidrepanocíticos/uso terapêutico , Estatura , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hidroxiureia/uso terapêutico , Masculino , Aumento de PesoAssuntos
Comportamento Infantil , Coagulantes/administração & dosagem , Hemartrose/prevenção & controle , Hemofilia A/tratamento farmacológico , Absenteísmo , Criança , Cognição , Efeitos Psicossociais da Doença , Esquema de Medicação , Escolaridade , Hemartrose/etiologia , Hemartrose/psicologia , Hemofilia A/complicações , Hemofilia A/psicologia , Humanos , Qualidade de Vida , Baixo Rendimento EscolarRESUMO
Hepatitis C virus (HCV) infection may be associated with neurocognitive deficits. The Hemophilia Growth and Development Study enrolled HIV-infected and HIV-uninfected patients and a group of nonhemophiliac siblings. After controlling for multiple factors, HCV monoinfection was not associated with deficits in adaptive behavior, intelligence, or attention/concentration.
Assuntos
Cognição , Hepatite C/fisiopatologia , Hepatite C/psicologia , Sistema Nervoso/fisiopatologia , Adaptação Psicológica , Adolescente , Adulto , Atenção , Criança , Estudos de Coortes , Humanos , InteligênciaRESUMO
BACKGROUND: Human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is a common and complex clinical problem in which loss of immunological control of HCV occurs, with increased HCV viral load and more aggressive liver disease. Cellular immune responses, particularly secretion of interferon gamma (IFN-gamma) appear to be important in the control of HCV, and a detectable HCV specific CD4 response is associated with clearance of the virus. HCV specific CD8+ T cell responses, weak in chronic HCV infection, have been shown to be further impaired in HIV coinfection and this CD8+ T cell deficiency is related to the decline in CD4 T cell count. AIMS: To compare the CD4 T cell response to HCV in HIV/HCV coinfected and HCV monoinfected individuals and to determine the relationship of responses with declining CD4 count. PATIENTS: The study subjects were a cohort of 68 HCV monoinfected and 67 HCV/HIV coinfected haemophiliac children and adolescents (the Hemophilia Growth and Development Study) who were followed for a seven year period. METHODS: We analysed IFN-gamma secreting CD4+ responses to HCV proteins and peptides and HIV p24 antigen using an ELISpot assay. RESULTS: We found a significant decrease in HCV specific responses among those who were HIV coinfected (10/67 v 36/68; p<0.0001) both in numbers of responders and frequency of specific cells. This did not appear to be closely related to CD4 count. CONCLUSIONS: The reduction in HCV specific CD4 T cells in coinfection provide a cellular mechanism for the loss of control of HCV in coinfected individuals, even in those with relatively preserved CD4+ T cell counts and CD4+ T cell responses to HIV.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/imunologia , Hepatite C Crônica/imunologia , Interferon gama/metabolismo , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade , Criança , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepacivirus/imunologia , Hepatite C Crônica/complicações , Humanos , Imunidade CelularRESUMO
The stromal-derived factor-1 (SDF-1) chemokine gene encodes the only natural ligand for CXCR4, the coreceptor for the pathogenic X4 HIV-1 strains. A single-nucleotide polymorphism (SNP) in the 3' untranslated region (SDF1-3'A=rs1801157) of SDF-1 was reported to be protective against infection and progression in some, but not other, epidemiological studies. To identify additional alleles that may influence HIV-1 infection and progression to AIDS, nine SNPs (including rs1801157) spanning 20.2 kb in and around the SDF-1 gene were genotyped in over 3000 African American (AA) and European American (EA) participants enrolled in five longitudinal HIV-1/AIDS natural cohort studies. Six or five haplotypes were present at frequencies greater than 5% in AA or EA, respectively. Six of the nine SNPs occur on only one common haplotype (>5%), while the remaining three SNPs were found on multiple haplotypes, suggesting a complex history of recombination. Among EA, rs754618 was associated with an increased risk of infection (OR=1.50, P=0.03), while rs1801157 (=SDF1-3'A) was associated with protection against infection (OR=0.63, P=0.01). In the MACS cohort, rs1801157 was associated with AIDS-87 (RH=0.31, P=0.02) and with death (RH=0.18, P=0.02). Significant associations to a single disease outcome were found for two SNPs and one haplotype in AA.
Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Quimiocinas CXC/genética , Infecções por HIV/genética , HIV-1/genética , Haplótipos , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/mortalidade , Adolescente , Adulto , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/estatística & dados numéricos , Alelos , Quimiocina CXCL12 , Criança , Estudos de Coortes , Progressão da Doença , Feminino , Frequência do Gene , Infecções por HIV/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida , Estados Unidos/epidemiologia , População Branca/genética , População Branca/estatística & dados numéricosAssuntos
Hemofilia A/genética , Alelos , Saúde da Família , Genoma Humano , Humanos , Desequilíbrio de Ligação/genéticaRESUMO
Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.
Assuntos
Hepacivirus , Hepatite C Crônica/genética , Imunidade Inata/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único/genética , Negro ou Afro-Americano , Estudos de Coortes , Haplótipos/genética , Haplótipos/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/terapia , Humanos , Interleucina-10/imunologia , População BrancaRESUMO
The aim of the study is to determine the causes and frequency of hospitalization in HIV-negative boys and adolescents with haemophilia and evaluate their impact on academic achievement. One hundred and twenty-six HIV-negative boys and adolescents were followed prospectively from 1989-96, at 14 comprehensive haemophilia treatment centres. One hundred and fifteen participants with haemophilia A or B were included in the investigation. These participants contributed an average of 57.8 months of follow-up. There were 203 hospitalizations in 65 participants and 50 participants were never hospitalized. Haemarthroses and soft tissue bleeds accounted for 46 and 44 causes of hospitalization. Central line infection was the third most common cause. Participants with inhibitor had the majority of central line infections and hospitalizations. Intracranial haemorrhage resulted in five hospitalizations in two participants. Other causes of bleeding accounted for 22% of hospitalizations. The median number of hospitalizations per year was 0.18. Duration of hospital stay was significantly related to lower spelling scores. Acute and chronic joint problems and soft tissue bleeds still account for the majority of hospitalizations. Positive inhibitor status was associated with higher numbers of hospitalizations and central line infections. Academic achievement was affected, to some degree, by length of hospital stay.
Assuntos
Hemofilia A/terapia , Hemofilia B/terapia , Hospitalização/estatística & dados numéricos , Adolescente , Criança , Escolaridade , Hemartrose/etiologia , Hemartrose/terapia , Hemofilia A/psicologia , Hemofilia B/psicologia , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos ProspectivosRESUMO
PURPOSE: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia. METHODS: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor. RESULTS: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13). CONCLUSIONS: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.