RESUMEN
The treatment of chronic hepatitis C has considerably changed with the introduction of recent direct acting antivirals. These antivirals have sustained virologic response (SVR) rates above 90â% as well as reduced toxicity and treatment duration. Therefore, current German guidelines recommend these interferon-free regimens as first-choice treatment. Nevertheless, recent developments were accompanied by a significant increase in treatment costs, which led to extensive discussions on reasonable pharmaceutical prices. The aim of the current study was to analyze the average treatment costs and costs per patient cured for guideline treatment recommendations. Analyses were stratified according to genotype, treatment status (naive/experienced), and presence/absence of cirrhosis. Costs were separated in (1.) basic diagnostic procedures, (2.) monitoring, and (3.) pharmaceuticals. The calculation is based on a remuneration scheme in the statutory health insurance system. In treatment-naïve non-cirrhotic patients, the average cost is 41â766â/SVR for the treatment with SOF/LDV calculated (PTV/r/OMV+DSV: 53â129â/SVR). In treatment-naive cirrhotic patients, costs were 60â323â/SVR (SOF/LDV+RBV) and 80â604â/SVR (PTV/r/OMV+DSV+RBV). Treatment-experienced genotype 1 patients had average costs of 60â366â/SVR for SOF/LDV treatment as well as 53â134â/SVR for PTV/r/OMV+DSV±RBV treatment (cirrhotic patients: 62â208â/SVR for SOF/LDV+RBV; 80â824â/SVR for PTV/r/OMV+DSV+RBV). The average treatment costs per SVR in treatment-naive genotype 1 patients are comparable to previous standard of care treatments and lower in treatment-experienced patients. In other genotypes, treatment costs and costs per cure are significantly higher compared to previous standard of care. However, long-term modelling studies show that new regimens are cost-effective.
Asunto(s)
Antivirales/economía , Fibrosis/economía , Fibrosis/prevención & control , Costos de la Atención en Salud/estadística & datos numéricos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/economía , Guías de Práctica Clínica como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/normas , Antivirales/uso terapéutico , Comorbilidad , Simulación por Computador , Femenino , Fibrosis/epidemiología , Alemania/epidemiología , Hepatitis C Crónica/epidemiología , Humanos , Interferones/economía , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos Económicos , Prevalencia , Adulto JovenRESUMEN
Viral hepatitis is a major public health problem affecting millions of people worldwide. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess outcomes and costs of treating patients with chronic hepatitis C in clinical practice in Germany. We carried out a prospective noninterventional study. Information on treatment outcomes, resource utilization and quality of life was provided by 281 physicians throughout Germany. Data of 3708 monoinfected HCV-patients treated between 2008 and 2011 were analysed. Therapy consisted of peginterferon/ribavirin. Mean age of patients was 43.7 years, 60.3% were male and estimated duration of infection was 13.6 years. Predominantly genotype 1 (61.3%) or 3 (28.5%) infections were observed. Sustained viral response (SVR)-rates in most frequently observed genotypes were 49.2% in GT-1 and 61.9% in GT-3 treatment-naive patients (Relapser: GT-1: 35.3% and GT-3: 57.3%; Nonresponder: GT-1: 25.0% and GT-3: 33.3%). Average treatment costs were lowest in treatment-naive patients (18 965) and higher in patients who failed previous treatments (relapsers: 24 753; nonresponders: 19 511). Differences according to genotype were observed. Average costs per SVR in treatment-naive patients were 44 744 for GT-1 and 22 218 for GT-3. Treatment was associated with a decrease in quality of life; post-treatment quality of life was higher in patients achieving SVR. Our insight on real-life treatment outcomes and costs can serve as a reference for a comparison with other treatments. There is high need for short-term and long-term cost-effectiveness analysis in real-life settings as newly introduced treatment strategies with direct acting antivirals result in high SVR-rates but are more costly.
Asunto(s)
Análisis Costo-Beneficio , Costos de la Atención en Salud , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/economía , Adulto , Antivirales/economía , Antivirales/uso terapéutico , Quimioterapia Combinada/economía , Femenino , Genotipo , Alemania , Humanos , Interferón-alfa/economía , Interferón-alfa/uso terapéutico , Masculino , Polietilenglicoles/economía , Polietilenglicoles/uso terapéutico , Estudios Prospectivos , Calidad de Vida , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéutico , Ribavirina/economía , Ribavirina/uso terapéutico , Resultado del TratamientoRESUMEN
The costs of a guideline-based treatment in chronic hepatitis C infected people are unknown. The goal of HCV therapy is to achieve a sustained viral response and thereby to reduce morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. This study analyses the costs of a guideline-based treatment based on the German guideline on the management of HCV infection. In addition, costs of newly introduced protease inhibitors were calculated. Costs for baseline diagnostics, monitoring and medical treatment were calculated according to the stage of the disease, the HCV genotype and viral response. Costs for baseline diagnostics account for â302.75 and monitoring accounts for â596 to â1173. Dual therapy with pegylated interferon and ribavirin results in average costs of â7709 to â34â692. Total costs of a guideline-based treatment range between â8,608 and â36â167 depending on HCV genotype and length of therapy. With the introduction of protease inhibitors for HCV genotype 1 patients, costs of pharmaceuticals have increased further. Triple-therapy with telaprevir accounts for â43â280 respectively â54â844. Costs for Boceprevir treatment range from â34â143 to â60â990. Due to increasing costs, health-economic evaluations gain significant relevance and should be considered when implementing new treatment strategies.
Asunto(s)
Antivirales/economía , Antivirales/uso terapéutico , Adhesión a Directriz/economía , Costos de la Atención en Salud/estadística & datos numéricos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/economía , Guías de Práctica Clínica como Asunto , Femenino , Alemania/epidemiología , Adhesión a Directriz/estadística & datos numéricos , Hepatitis C Crónica/epidemiología , Humanos , Masculino , PrevalenciaRESUMEN
BACKGROUND: In medically ill patients, no contemporary double-blind head-to-head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. OBJECTIVES: To compare the efficacy and safety of certoparin with those of UFH. PATIENTS/METHODS: In this double-blind, randomized, controlled trial, acutely ill, non-surgical patients aged > or = 70 years were randomized to certoparin (3000 U of anti-factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death, and was assessed by a blinded central adjudication committee. Non-inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. RESULTS: Three thousand two hundred and thirty-nine patients aged 78.8 + or - 6.3 years were treated for 9.1 + or - 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of - 0.59% [95% confidence interval (CI) -2.09 to 0.92; P < 0.0001 for non-inferiority], and an OR of 0.87 (95% CI 0.60-1.26; P = 0.0001 for non-inferiority). Major bleeding occurred in 0.43% of certoparin-treated patients and 0.62% of UFH-treated patients (OR 0.69; 95% CI 0.26-1.83). Any bleeding occurred at 3.20% in certoparin-treated patients vs. 4.58% in UFH-treated patients (OR 0.69; 95% CI 0.48-0.99; P < 0.05), and 5.73% of certoparin-treated patients and 6.63% of UFH-treated patients experienced serious adverse events. All-cause mortality was 1.27% in certoparin-treated patients and 1.36% in UFH-treated patients. CONCLUSIONS: In acutely ill, non-surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti-FXa once daily) was non-inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.
Asunto(s)
Anticoagulantes/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina/uso terapéutico , Tromboembolia/prevención & control , Enfermedad Aguda , Anciano , Método Doble Ciego , HumanosRESUMEN
In Germany up to 800,000 persons are chronically infected with the hepatis C virus. This chronic disease is correlated with a significant morbidity and mortality. This is a consequence of the development of liver cirrhosis and hepatocellular carcinoma in a substantial proportion of the patients. Health quality of life is also affected by the infection. There are reliable standards available for diagnosis and treatment. Antiviral treatment is highly effective and the combination of pegylated interferon alpha with ribavirin leads to a sustained viral eradication in about 60% of the cases. The treatment is also cost-effective and results in an increased life expectancy. Costs for HCV treatment are favourable in comparison to other well accepted therapies and interventions and a reduction of future costs can be expected.Thus, active screening for HCV infected persons should be intensified to improve the quality of medical care. Early and broad treatment is potentially able to reduce the future burden of HCV-related diseases.
Asunto(s)
Costo de Enfermedad , Sistemas de Apoyo a Decisiones Clínicas , Brotes de Enfermedades/economía , Brotes de Enfermedades/prevención & control , Hepatitis C Crónica/economía , Hepatitis C Crónica/terapia , Medicina Social , Enfermedad Crónica , Atención a la Salud/economía , Atención a la Salud/estadística & datos numéricos , Alemania/epidemiología , Hepatitis C Crónica/mortalidad , Humanos , Modelos EconómicosRESUMEN
Based on the German Hepatitis C Model (GEHMO) we developed a Hepatitis C Policy Model and applied it to the heterogeneous German hepatitis C population within the German health care context. We used Markov cohort simulation to predict absolute clinical and economic outcomes for a 20-year time horizon. For the cost-effectiveness analysis, a lifelong time horizon was used. Four different strategies were compared: (1) no antiviral treatment, (2) interferon monotherapy, (3) combination therapy with interferon plus ribavirin, and (4) combination therapy with pegylated interferon plus ribavirin. Based on our model, antiviral therapy with pegylated interferon and ribavirin could prevent about 17,000 cases of cirrhosis, 580 liver transplants, and 7,600 HCV-related deaths and is expected to save about 53,000 life years at total costs of 1.3 billion Euros within the next 20 years. Pegylated interferon plus ribavirin was the most effective treatment with an incremental cost-utility ratio of 23,000 Euros per quality-adjusted life year saved.
Asunto(s)
Atención a la Salud/economía , Costos de la Atención en Salud/estadística & datos numéricos , Hepatitis C Crónica/economía , Hepatitis C Crónica/epidemiología , Modelos Económicos , Enfermedad Crónica , Análisis Costo-Beneficio/métodos , Toma de Decisiones , Técnicas de Apoyo para la Decisión , Economía Médica , Alemania/epidemiología , Humanos , Infecciones/economía , Infecciones/epidemiología , Proyectos de InvestigaciónRESUMEN
The only way to prevent the late sequelae of chronic HCV infection--liver cirrhosis or HCC--is by early and specific antiviral therapy. A prerequisite is the identification of HCV-infected persons in the general population. To accomplish this a screening concept that includes all patients with exposure risks or elevated serum transaminases is needed.
Asunto(s)
Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Hepatitis B Crónica/diagnóstico , Hepatitis C Crónica/diagnóstico , Pruebas de Función Hepática , Estudios Transversales , Árboles de Decisión , Diagnóstico Diferencial , Alemania , Hepatitis B Crónica/epidemiología , Hepatitis C Crónica/epidemiología , Humanos , PronósticoAsunto(s)
Antivirales , Costos de la Atención en Salud , Hepatitis Viral Humana/tratamiento farmacológico , Hepatitis Viral Humana/economía , Esperanza de Vida , Antivirales/economía , Antivirales/uso terapéutico , Enfermedad Crónica , Análisis Costo-Beneficio , Progresión de la Enfermedad , Quimioterapia Combinada , Alemania , Hepatitis Viral Humana/mortalidad , Humanos , Calidad de Vida , Resultado del TratamientoRESUMEN
We have previously studied the effect of three different treatment regimens with interferon (IFN)-alpha alone or in combination with amantadine or ribavirin on viral kinetics in the first month of therapy. To understand the regulation of cytokine immune response during early inhibition of HCV replication, we analysed the longitudinal profile of proinflammatory markers (soluble TNFRs), of type 1 cytokines [IFN-gamma and interleukin (IL-12)], and of a type 2 cytokine (IL-10). Twenty-two chronic hepatitis C patients received daily therapy for 6 months. Sera were collected at baseline, at 6, 12, 24, 30 and 48 h and at the 3rd, 7th, 15th and 30th days of treatment. All cytokines and receptors were evaluated by enzyme linked immunosorbent assay (ELISA). At baseline, a correlation was found between the two soluble TNFRs (P < 0.0001) and between the soluble TNFRs and ALT levels (P < 0.003), as shown previously. Regardless of the type of treatment, lower levels of soluble TNFR-p75 were present from day 3 in patients who had significant virus decay at day 30 (P < 0.01). Baseline IL-10 levels correlated with TNFR-p75 (P < 0.01) and with treatment response (P < 0.05) and a significant IL-10 reduction from baseline was observed from day 3 among responders, irrespective of the type of treatments (P < 0.05). IL-12 and IFN-gamma levels did not differ according to treatment or outcome. These findings suggest a pivotal role for IL-10 in orchestrating the antiviral immune response. Its early decline can favour the shift from a Th2 to a Th1 immune response, which has been shown to be associated with a long-term virological response to treatment.
Asunto(s)
Citocinas/metabolismo , Hepatitis C Crónica/terapia , Interferón-alfa/administración & dosificación , Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Amantadina/uso terapéutico , Antivirales/uso terapéutico , Biomarcadores/sangre , Terapia Combinada , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Humanos , Inmunoterapia Activa , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-12/sangre , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/sangre , Ribavirina/uso terapéutico , Estadísticas no Paramétricas , Carga ViralRESUMEN
BACKGROUND: Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. AIMS: To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. METHODS: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. CONCLUSIONS: Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.
Asunto(s)
Antivirales/economía , Antivirales/uso terapéutico , Costos de la Atención en Salud , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/economía , Interferón-alfa , Interferón-alfa/uso terapéutico , Polietilenglicoles , Ribavirina/uso terapéutico , Adulto , Análisis Costo-Beneficio , Costos de los Medicamentos , Quimioterapia Combinada , Femenino , Alemania , Humanos , Interferón alfa-2 , Interferón-alfa/economía , Esperanza de Vida , Masculino , Cadenas de Markov , Persona de Mediana Edad , Años de Vida Ajustados por Calidad de Vida , Proteínas Recombinantes , Ribavirina/economía , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
Butyrate, a short-chain fatty acid released by colonic bacteria and administered therapeutically in inflammatory bowel diseases, exerts immunomodulatory properties. The aim of the study was to determine the functional consequences of butyrate exposure on the proinflammatory responsiveness of human intestinal epithelial cells (IEC). IL-8 promoter activity in IEC pretreated with butyrate then exposed to proinflammatory stimuli was assayed by transfection of luciferase constructs. IL-8 secretion was determined by ELISA and neutrophil migration by flow cytometry. Receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Butyrate modulated proinflammatory IL-8 secretion differentially in Caco-2 and HT-29 cells on the transcriptional level. Pointing to the potentially underlying mechanism of increased IL-1 beta-stimulated IL-8 secretion in HT-29 cells, butyrate up-regulated IL-1RI mRNA but not IL-1RII. Butyrate pretreatment of IEC lines stimulated by IL-1 beta modulated neutrophil migration significantly: reduction towards Caco-2 and enhancement towards HT-29/p cells. Pharmacological inhibition of protein tyrosine phosphatases or treatment with mesalamine or sulphasalazine diminished IL-1 beta-stimulated IL-8 secretion by butyrate-exposed HT-29 cells substantially. Immunomodulatory effects of butyrate on IEC are functionally relevant for neutrophil migration. Pharmacological inhibition of enhanced IL-1 beta-mediated IL-8 secretion in a subpopulation of IEC may improve the clinical efficacy of butyrate.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Butiratos/uso terapéutico , Interleucina-1/inmunología , Interleucina-8/metabolismo , Mucosa Intestinal/inmunología , Antiinflamatorios no Esteroideos/uso terapéutico , Células CACO-2 , Quimiotaxis de Leucocito/efectos de los fármacos , Células HT29 , Humanos , Interleucina-8/genética , Mucosa Intestinal/efectos de los fármacos , Mesalamina/uso terapéutico , ARN Mensajero/análisis , Receptores de Interleucina-1/genética , Sulfasalazina/uso terapéutico , Transcripción GenéticaRESUMEN
Interleukin-12 (IL-12) has many antiviral properties both in vitro and in vivo, such as enhancing cytotoxic lymphocyte reaction, promoting Th1-helper cell response and inducing interferon-gamma - (IFN-gamma) production. The present study investigated possible antiviral effects of recombinant human IL-12 in vivo in 11 chronic hepatitis patients treated with rHuIL-12 subcutaneously in 3 different dosages (0.03, 0.1, 0.5 microg/kg) once weekly for a period of 10 weeks. ELISA was employed to determine before onset of therapy the serum concentrations of IL-12, IL-12p40, IFN-gamma, IL-4, IL-10, tumor mecrosis factor-alpha (TNF-alpha), TNFR p55 and p75, as well as on days 3, 5, 8, 10, 12, 15, 17, 22 after onset of therapy and subsequently weekly until the end of the treatment period and at the end of the 12 months' postobservatory period. The HCV-RNS serum concentration was determined by means of an RT-PCR method. Two to three days after the subcutaneous rHuIL-12 injections there was a transient significant rise of n the serum concentrations of IL-12, IL-12p40, IFN-gamma and TNFR p55, followed by a decrease to the original level. The increases of the IL-12 and IFN-gamma serum concentrations were dose-dependent. In patients where there was a decline of the HCV-RNS concentration in the serum we confirmed a trend to higher IL-12 serum concentrations. The serum levels of IL-2, TNF-alpha and IL-10 fluctuated only during the treatment period. The present study showed that a once-a-week injection of rHuIL-12 results in a merely transient rise of the IL-12, IL-12-p40- and IFN-gamma serum concentrations. This may offer an explanation for the unsatisfactory clinical efficiency of the substance.
Asunto(s)
Citocinas/sangre , Hepatitis C Crónica/tratamiento farmacológico , Interleucina-12/uso terapéutico , Receptores del Factor de Necrosis Tumoral/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Adulto , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/inmunología , Humanos , Interleucina-12/efectos adversos , Interleucina-12/sangre , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/sangre , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Células TH1/inmunología , Células Th2/inmunología , Resultado del TratamientoRESUMEN
Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/metabolismo , Aminoácidos/metabolismo , Seropositividad para VIH/metabolismo , Síndrome de Emaciación por VIH/metabolismo , Pierna/fisiología , Adulto , Aminoácidos/sangre , Arginina/metabolismo , Glucemia/metabolismo , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Eritrocitos/metabolismo , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Femenino , Glicerol/metabolismo , Humanos , Insulina/sangre , Interleucina-6/sangre , Cetonas/sangre , Cetonas/metabolismo , Ácido Láctico/sangre , Lisina/metabolismo , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Nitrógeno/metabolismo , Ácido Pirúvico/sangreRESUMEN
Endothelin-1 is the most potent vasoconstrictor known to date. This peptide is believed to play a pathophysiological role in the development of vasospasm, the most important complication of subarachnoid hemorrhage (SAH). In the present study we investigated the release of endothelin-1 in SAH and analyzed the cellular source of this peptide. At a protein and mRNA level we were able to show that endothelin-1 is produced by mononuclear leukocytes. Complementary in vitro studies revealed that aging and subsequent hemolysis of blood is sufficient to induce production of endothelin-1 by mononuclear leukocytes. Thus, cerebrospinal fluid-derived mononuclear leukocytes are a source of endothelin-1 in patients suffering from SAH. This finding may have important therapeutic implications as anti-leukocyte strategies could prevent cerebrovascular complications in SAH patients.
Asunto(s)
Endotelina-1/sangre , Endotelina-1/metabolismo , Hemorragia Subaracnoidea/metabolismo , Adulto , Anciano , Aneurisma/sangre , Aneurisma/líquido cefalorraquídeo , Aneurisma/diagnóstico , Velocidad del Flujo Sanguíneo , Isquemia Encefálica/sangre , Isquemia Encefálica/líquido cefalorraquídeo , Isquemia Encefálica/diagnóstico , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Most patients with alcohol induced cirrhosis (AC) and chronic endotoxinaemia are not suffering from clinically evident systemic inflammatory reactions. This may be due to altered gene expression of cytokines, possibly related to endotoxin (for example, tolerance and sensitisation). Interleukin 18 (IL-18; interleukin gamma inducing factor) modulates local cytokine production in response to endotoxin (lipopolysaccharide (LPS)). AIM: To investigate the systemic immune response of patients with AC and to see if unstimulated peripheral blood mononuclear cells (PBMC) from patients with AC are activated and contribute to gene expression of IL-18. METHODS: Plasma levels of endotoxin (LPS) and serum levels of IL-18 were measured by enzyme linked immunoassay and the amoebocyte lysate test in 74 abstinent patients with different stages of AC (Child-Pugh stage A, n=18; B, n=22; C, n=34) and compared with healthy controls (n=43). Gene expression of IL-18 was assessed by semiquantitative reverse transcription-polymerase chain reaction in freshly isolated unstimulated PBMC of a subgroup of 14 patients with AC compared with five healthy controls. RESULTS: Gene expression of IL-18 specific mRNA in unstimulated PBMC was significantly enhanced in patients with advanced AC (Child-Pugh stage C) and correlated with plasma LPS and serum CD14 levels (Spearman rank correlation factors r=0.76 and r=0.72). Serum concentrations of IL-18 were also elevated compared with healthy controls (p<0.001) but correlation with serum levels of CD14 and plasma levels of LPS was much weaker compared with mRNA data (Spearman rank correlation factors r=0.47 and r=0.26). CONCLUSIONS: Our in vivo data suggest a presensitisation of "unstimulated" PBMC in the circulation of patients with AC by endotoxin. The term "unstimulated" may be inadequate in patients with AC. Further investigations are needed to define the exact mechanisms and localisation of sensitisation of PBMC in vivo.
Asunto(s)
Interleucina-18/metabolismo , Leucocitos Mononucleares/metabolismo , Cirrosis Hepática Alcohólica/sangre , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Expresión Génica , Humanos , Receptores de Lipopolisacáridos/sangre , Lipopolisacáridos/sangre , Masculino , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no ParamétricasRESUMEN
Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF)-alpha) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH.
Asunto(s)
Arterias Cerebrales/fisiopatología , Circulación Cerebrovascular/fisiología , Citocinas/sangre , Hemorragia Subaracnoidea/sangre , Hemorragia Subaracnoidea/fisiopatología , Vasoespasmo Intracraneal/sangre , Vasoespasmo Intracraneal/fisiopatología , Adulto , Anciano , Citocinas/líquido cefalorraquídeo , Citocinas/fisiología , Femenino , Humanos , Inflamación/sangre , Inflamación/fisiopatología , Interleucina-1/sangre , Interleucina-1/líquido cefalorraquídeo , Interleucina-1/fisiología , Interleucina-6/sangre , Interleucina-6/líquido cefalorraquídeo , Interleucina-6/fisiología , Masculino , Persona de Mediana Edad , Pronóstico , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Bacteria and bacterial antigens strongly induce cytokine secretion by peripheral blood leukocytes and thereby initiate an inflammatory cascade with potentially deleterious consequences for the host. The present study focussed on receptors and signal transduction pathways involved in activation of interleukin (IL)-18 by heat-inactivated Gram-positive Staphylococcus aureus Cowan strain I (SAC). Similarly to IL-12/IL-12p40, IL-10 and IFN-gamma, SAC dose-dependently activated IL-18. Secretion of IL-18 was independent of functional activity of IL-10, IL-12 or IFN-gamma. Lipoteichoic acid (LTA), a structural component of SAC, was not sufficient for activation of IL-18, while it dose-dependently induced IL-10. In contrast to IL-12, blockade of CD14 only partially diminished secretion of IL-18 and did not affect secretion of IL-10, suggesting involvement of other receptors (e.g., Toll-like receptors) in SAC responses. Further down-stream however, secretion of IL-10, IL-12 and IL-18 was uniformly inhibited by blockade of G-protein-mediated kinase activation by mastoparan. Secretion of IL-18 required phosphatidylinositol-3'-kinase, and secretion of IL-12 phosphotyrosine kinase activity. The data demonstrate that SAC potently activates secretion of IL-18 by peripheral blood mononuclear cells with differential involvement of cell-surface receptors and signal transduction pathways as compared to other natural killer- and T cell-promoting cytokines.
Asunto(s)
Interleucina-18/metabolismo , Monocitos/metabolismo , Neutrófilos/metabolismo , Staphylococcus aureus/fisiología , Dactinomicina/farmacología , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas In Vitro , Interferón gamma/sangre , Interleucina-18/sangre , Interleucina-18/genética , Receptores de Superficie Celular/fisiología , Transducción de Señal , Transcripción Genética/efectos de los fármacosRESUMEN
IL-18 shares activities with IL-12 in generating T-helper 1 cells and cytokine response. It mediates LPS/endotoxin lethality by IL-12 independent interferon-gamma synthesis and it induces bacteria-related organ failure. As peripheral blood mononuclear cells (PBMC) are potent producers of IL-18, we studied the regulation of IL-18 upon exposure to LPS and Staphylococcus aureus (SAC) in vitro. Freshly isolated PBMC constitutively expressed IL-18 mRNA. After unstimulated preincubation for 48 h, however, IL-18 transcripts were nearly not detectable by RT-PCR, but inducible by LPS or SAC (P<0.01). Both LPS and SAC were potent stimuli of IL-18 protein secretion (P<0.01). LPS-mediated IL-18 gene expression and secretion was CD14-dependent and significantly inhibited by co-incubation of PBMC with neutralizing CD14 antibody (P<0.01). We conclude that LPS-driven IL-18 is dependent on the expression of costimulatory factors and that IL-18 inhibition might attenuate IL-18-related toxic effects.
Asunto(s)
Endotoxinas/farmacología , Interleucina-18/metabolismo , Leucocitos Mononucleares/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Staphylococcus aureus/metabolismo , Adulto , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.