Diffusive vs. convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome

OBJECTIVE: To compare two forms of continuous renal replacement therapy, continuous venovenous hemofiltration (CVVH) vs. continuous venovenous hemodialysis (CVVHD), in terms of the removal of inflammatory mediators from the blood of patients with systemic inflammatory response syndrome and acute renal failure. DESIGN: Randomized crossover, clinical study. SETTING: University teaching hospital. PATIENTS: Thirteen patients with systemic inflammatory response syndrome and acute renal failure receiving continuous renal replacement therapy. INTERVENTION: Patients were randomized to receive either convective clearance using CVVH or diffusive clearance using CVVHD for the first 24 hrs, followed by the other modality for 24 hrs. All treatments utilized AN69 hemofilters. CVVH was performed with an ultrafiltration rate of 2 L/hr and CVVHD with a dialysis outflow rate of 2 L/hr. MEASUREMENTS AND MAIN RESULTS: Plasma and ultrafiltrate concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, and sL-selectin were measured at 0, 1, 3, 6, 12, and 24 hrs by radioimmunoassay. Plasma endotoxin concentrations were also measured at 0, 12, and 24 hrs by chromogenic assay. CVVH was associated with a 13% decrease in plasma TNF-alpha concentrations compared with a 23% increase while on CVVHD (p < .05). Mean plasma concentrations of IL-6, IL-10, and sL-selectin were unchanged over time and between therapies. Only minimal amounts of mediators were recovered in the effluents with either therapy except for IL-6. The clearances for IL-6 were different between therapies, 1.9+/-0.8 (SD) mL/min for CVVHD and 3.3+/-1.5 mL/min for CVVH, (p< .01). Plasma endotoxin concentrations were not different between therapies. CONCLUSION: CVVH resulted in a decrease in plasma TNF-alpha concentrations as compared with CVVHD, while the type of transport mechanism used did not influence plasma concentrations of IL-6, IL-10, soluble L-selectin, or endotoxin. Differences in clearance for IL-6 between CVVH and CVVHD did not translate into significant changes in circulating IL-6 concentrations.     

Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus

Status asthmaticus (SA) is an acute respiratory failure combining an acute bronchospastic reaction with a severe airway inflammation. We previously reported an important influx of neutrophils and an increased secretion of interleukin-8 (IL-8) in patients with SA. The aim of this prospective study was to evaluate in bronchial lavage (BL) of patients with SA (n = 9) under mechanical ventilation (MV) the concentrations of cytokines and related mediators which have the ability to modulate inflammation, either proinflammatory (interleukin-1beta [IL-1beta], IL-6, tumor necrosis factor-alpha [TNF-alpha]), or anti-inflammatory mediators (IL-10, transforming growth factor-beta1 [TGF-beta1]), interleukin-1 receptor antagonist [IL-1Ra], soluble TNF receptor I and II [sTNFRI and II]). To determine the relative importance of both pro- and anti-inflammatory mediators, the net inflammatory activity was analyzed by the capacity of BL fluids (BLF) to increase intercellular adhesion molecule-1 (ICAM-1) expression in the human lung A549 epithelial cell line. These data were compared with those obtained from patients who required MV without respiratory disease (V, n = 4), controlled asthma (A, n = 11), and nonsmoking healthy volunteers (C, n = 8). Levels of IL-1, IL-6, TNF-alpha, and of the active form of TGF-beta1 were significantly higher in SA compared with the other groups. The concentrations of IL-1Ra, IL-10, the latent form of TGF-beta1, and of the sTNFRI and II were not significantly different between SA and V, albeit higher in SA than in A and C. The ratio between IL-1Ra and IL-1beta was significantly higher in patients with SA compared with the other groups, whereas there was no difference for the ratio between both types of sTNFR and TNF-alpha. Despite a marked increase of anti-inflammatory mediators in BL from patients with SA, the net inflammatory activity was found to be proinflammatory and mainly due to the presence of bioactive IL-1beta (79% inhibition of ICAM-1 expression with anti-IL-1beta antibodies) and to a lesser extent TNF-alpha (32% inhibition with anti-TNF-alpha antibodies).     

Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group

OBJECTIVE: To assess the value of measuring circulating concentrations of mediators (endotoxin, tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], and interleukin-6[IL-6]) and their endogenous antagonists (antiendotoxin core antibody [EndoCAb], interleukin-1 receptor antagonist [IL-1ra], and soluble TNF receptors [sTNF-R]) in predicting mortality and organ failure in sepsis syndrome. DESIGN: Cohort study with a follow-up period of 30 days. SETTING: Intensive therapy units of five tertiary referral centers in Scotland. SUBJECTS: A total of 146 intensive therapy unit patients with sepsis syndrome underwent repeated sampling during a 10-day period following admission to an intensive therapy unit. MAIN OUTCOME MEASURES: Circulating concentrations of mediators and antagonists were compared in survivors and nonsurvivors. RESULTS: Median Acute Physiology and Chronic Health Evaluation II score was 23 (range, 8 to 40). Mortality at 30 days was 49%. On entry to the study, circulating endotoxin was detected in 66% of patients, TNF-alpha in 14%, and IL-1 beta in 29%. Levels did not predict mortality or organ failure. Patients with IL-6 concentrations in excess of 3000 pg/mL had an increased mortality rate (64% vs 40%, P = .02). The incidence of IgG EndoCAb depletion on entry to the study was 26% in nonsurvivors and 10% in survivors (P = .02). Initial concentrations of both type I and type II sTNF-R were significantly higher in nonsurvivors (P < .01). Initial circulating IL-1ra concentrations were not of value in predicting mortality. Cytokine antagonists were present in concentrations 30- to 100,000-fold greater than their corresponding cytokine. CONCLUSION: The observed high circulating levels of the cytokine antagonists IL-1ra and sTNF-R and the relatively small proportion of patients developing EndoCAb depletion may contribute to the limitations of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines.     

IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation

BACKGROUND AND OBJECTIVE: The relationship between cytokine concentrations and transplant-related complications has been studied in bone marrow transplant patients. The changes in TNF-alpha, IL-1 and IL-6 concentrations after transplantation are well documented in the literature but this is not the case for IL-8. The purpose of the present study was to investigate prospectively the plasma concentration of these cytokines and their relationship to transplant-related complications. DESIGN AND METHODS: Pro-inflammatory cytokine (TNF-alpha, IL-1, IL-6 and IL-8) levels in plasma were determined in a group of 53 patients undergoing hematopoietic progenitor transplantation. Plasma samples were collected weekly from day -7 to day +35 and stored at -70 degrees C until assayed by ELISA. The major transplant-related toxicities registered were: veno-occlusive disease (VOD), acute graft-versus-host disease (GVHD), infectious episodes, renal failure and mucositis. RESULTS: In spite of the great variability of plasma cytokine profiles between the different patients, we came to various conclusions. Patients' TNF-alpha and IL-1 concentrations correlated well over time. IL-6 and IL-8 profiles were similar and correlated well with febrile episodes. In some cases, an increase in IL-6 preceded hematologic recovery. In our study, increased levels of TNF-alpha, IL-6 and especially IL-8 correlated with hepatic or renal dysfunction as evaluated by increased bilirubin and creatinine in plasma, while pulmonary complications correlated only with increased IL-6 levels. Allogeneic transplant patients had a tendency to have higher TNF-alpha concentrations than autologous transplant patients, probably because an allogeneic transplant is associated with more transplant-related toxicity. Basal disease usually had no effect on cytokine profiles. INTERPRETATION AND CONCLUSIONS: IL-6 and IL-8 were the only cytokines studied whose increase correlated with febrile episodes. High IL-8 values may be a useful predictor of renal dysfunction and pulmonary disease and seems to trigger off high IL-6 levels. Plasma TNF-alpha and IL-1 concentrations during the posttransplant period have not been shown to be predictive of the development of transplant-related complications, and none of the profiles was recognized to be specific for a particular complication in this study.     

Increased plasma concentrations of serum amyloid A: an indicator of the acute-phase response after cardiopulmonary bypass

OBJECTIVES: To assess the expression of mixed and hepatic venous serum amyloid A (SAA) concentrations and its relationship to plasma concentrations of C-reactive protein, interleukin-6 (IL-6), and endotoxin during and after cardiopulmonary bypass (CPB). DESIGN: Prospective, consecutive sample with repeated measurements. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: Twenty patients who underwent elective coronary bypass grafting. INTERVENTIONS: A radial artery catheter, pulmonary artery catheter, and right hepatic vein catheter were inserted. Blood samples were collected to determine the different mediators, lactate concentrations, and oxygen saturations. MEASUREMENTS AND MAIN RESULTS: After induction of anesthesia, baseline values were obtained and the following parameters were determined 20 mins after onset of CPB, 20 mins after termination of CPB, at admission to the ICU, and 6, 8, 12, and 24 hrs later: hemodynamics, body core temperature, hepatic venous oxygen saturation, and mixed and hepatic venous lactate, endotoxin, interleukin (IL)-6, C-reactive protein (CRP), and SAA concentrations. Endotoxin and IL-6 plasma concentrations increased during CPB, peaked 6 hrs after admission to the ICU (endotoxin: 23.1 +/- 6.2 pg/mL; IL-6: 646 +/- 104 pg/mL), and decreased thereafter; SAA and CRP concentrations began to increase after 6 and 8 hrs, respectively, with the highest concentrations reached 24 hrs postoperatively (CRP: 14 +/- 3.6 mg/L; SAA: 668 +/- 114 micrograms/mL). Lactate concentrations began to increase 20 mins after CPB, and continued to increase until 12 hrs postoperatively. There were no significant differences between mixed and hepatic venous values of endotoxin, IL-6, CRP, SAA, and lactate (p < .05). Body core temperature, which was < 37.5 degrees C before surgery for all patients, increased 6 hrs after admission to the ICU and peaked 12 hrs postoperatively (38.3 +/- 1.1 degrees C). Hepatic venous oxygen saturation did not change. Correlations were obtained between IL-6 values and heart rate (r2 = .20; p < .005), and endotoxin concentrations and systemic vascular resistance (r2 = .18; p < .001). Body core temperature correlated significantly closer with SAA (r2 = .52; p < .0001) values than with IL-6 (r2 = .27; p < .0001) or CRP (r2 = .16; p < .001) values (p < .05). CONCLUSIONS: SAA is an additional and sensitive marker of the acute-phase response following CPB; the increase in SAA concentrations parallels the temporary increase in body core temperature and is preceded by endotoxemia and IL-6 secretion.     

Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure

OBJECTIVE: This study investigates the course of serum cytokine levels in patients with multiple trauma, patients with a ruptured abdominal aortic aneurysm (AAA), and patients undergoing elective AAA repair and the relationship of these cytokines to the development of adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). SUMMARY BACKGROUND DATA: Severe tissue trauma, hemorrhagic shock, and ischemia-reperfusion injury are pathophysiologic mechanisms that may result in an excessive uncontrolled activation of inflammatory cells and mediators. This inflammatory response is thought to play a key role in the development of (remote) cell and organ dysfunction, which is the basis of ARDS and MOF. METHODS: The study concerns 28 patients with multiple trauma, 20 patients admitted in shock because of a ruptured AAA, and 18 patients undergoing elective AAA repair. Arterial blood was serially sampled from admission (or at the start of elective operation) to day 13 in the intensive care unit, and the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 were determined. RESULTS: Twenty-two patients died, 15 within 48 hours and 7 after several weeks, as a result of ARDS/MOF. At hospital admission and after 6 hours, these nonsurvivors had significantly higher plasma TNF-alpha and IL-1 beta levels than did the survivors. At the same measuring points, TNF-alpha and IL-1 beta were significantly more elevated in patients with ruptured AAA than in traumatized patients. However, IL-6 was significantly higher in the traumatized patients. In 10 patients, ARDS/MOF developed, and 41 had an uncomplicated course in this respect. Those with ARDS/MOF exhibited significantly different cytokine patterns in the early postinjury phase. TNF-alpha and IL-1 beta levels were higher mainly on the first day of admission; IL-6 concentrations were significantly elevated in patients with ARDS/MOF from the second day onward. The latter cytokine showed a good correlation with the daily MOF score during the whole 2-week observation period. CONCLUSIONS: In the early postinjury phase, higher concentrations of these cytokines are associated, not only with an increased mortality rate, but also with an increased risk for subsequent ARDS and MOF. These data therefore support the concept that these syndromes are caused by an overwhelming autodestructive inflammatory response.     

Leukemic pleural effusion in B-cell prolymphocytic leukemia

BACKGROUND: Proinflammatory mediators that include tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) and anti-inflammatory mediators such as interleukin-10 (IL-10) modulate the immune response to endotoxemia. IL-10 downregulates the production of TNF-alpha and MIP-2. Acute lung injury may occur secondary to neutrophil chemotaxis mediated by chemokine MIP-2. We studied the temporal relationship of TNF-alpha, MIP-2, and IL-10 in rat endotoxemia and correlation of MIP-2 concentrations with acute lung injury. METHODS: Ten ventilated rats were randomized to receive an intravenous infusion of 2 mg/kg Escherichia coli lipopolysaccharide (n = 6) or saline placebo (n = 4). Blood pressure was continuously monitored and arterial blood was obtained for lactate, blood gas, TNF-alpha, IL-10, and MIP-2 measurements at baseline, 2, 4, and 5.5 hours after LPS or saline infusion. RESULTS: Endotoxemia resulted in hypotension, lactic acidemia, and increased alveolar-arterial oxygen gradient (A-a O2 gradient) compared with the placebo group. TNF-alpha, MIP-2, and IL-10 levels were increased 2 hours after endotoxemia. Subsequently, TNF-alpha levels declined while IL-10 and MIP-2 levels remained elevated. Control rats had no significant increase in cytokine production at any time point. MIP-2 concentrations correlated with A-a O2 gradient, an indicator of lung injury (r = 0.56, p < 0.001). CONCLUSIONS: MIP-2, possibly released by TNF-alpha stimulation of macrophages, is associated with acute lung injury possibly by inducing neutrophil chemotaxis. IL-10 may exert its counter-inflammatory response by inhibiting the release of TNF-alpha in endotoxemia.     

A close association of prognosis with effect of interferon in HBV carriers developing acute severe exacervation

We have treated 19 HBV carriers who developed acute severe exacerbation using interferon and immunosuppressive agents. Of these 14 patients developed fulminant hepatic failure. Of 10 patients with positive result for serum HBV DNA polymerase before the start of te treatment, five patients in whom HBV DNA polymerase turned negative and one patient whose HBV DNA polymerase level fluctuated in a low abnormal range after the start of the treatment survived. While, four patients whose HBV DNA polymerase level remained high after the start of interferon treatment died. Thus, it is suggested that suppression of HBV virus replication is closely related to prognosis in HB carriers developing acute severe exacervation of hepatitis.     

New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone

Typhoid fever is often associated with abnormal liver biochemical tests, but severe hepatic involvement with a clinical feature of acute hepatitis is a rare complication. There have been more than 150 cases of salmonella hepatitis reported from both developed and developing countries. The documented incidence varies widely from less than 1% to 26% patients with enteric fever. The possible associated factors for development of salmonella hepatitis are virulence of the organisms, delayed treatment and poor general health of the patients. The pathogenesis of severe hepatic involvement in salmonella infection may be multifactorial and includes endotoxin, local inflammatory and/or host immune reactions. Clinical jaundice in salmonella hepatitis usually occurs within the first 2 weeks of the febrile illness. Hepatomegaly and moderate elevation of transaminase levels are common findings. Extreme hepatic dysfunction with hepatic encephalopathy is a rare coexisting complication in salmonella hepatitis. A positive culture for salmonella from blood or stool is essential to differentiate salmonella hepatitis from other causes of acute hepatitis. Hepatic pathology is characterized by the presence of typhoid nodules with marked hyperplasia of reticuloendothelial cells. The prognosis is usually good as salmonella hepatitis responds well to a specific antibiotic therapy and juandice resolves with clinical improvement. The clinical course can be severe with a mortality rate as high as 20%, particularly with delayed treatment or in patients with other complications of salmonella infection. As enteric fever is a common infection, the recognition of salmonella hepatitis is of clinical importance.     

Effect of training on general practitioners'' use of a brief intervention for excessive drinkers

During recent years the outcome of acute hepatitis A in chronic liver disease has been discussed controversially. Data from large hepatitis A epidemics and surveillance data from the United States suggest a significantly higher risk of fatal outcome in patients with chronic hepatitis B. Patients with chronic active hepatitis or liver cirrhosis seem to be at highest risk, while HBsAg carriers may exhibit a benign course of the disease. Patients with chronic hepatitis C also seem to have a significantly higher risk of fulminant hepatic failure when superinfected with hepatitis A. The recently reported unsuspected coincidence of autoimmune markers with a fulminant course of hepatitis A in those patients needs to be confirmed. Vaccination against hepatitis A in patients with chronic liver disease has been shown to be safe and effective.     

Posttransplantation chronic hepatitis in fulminant hepatic failure

Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.     

Proinflammatory cytokines lowering erythropoietin production

The plasma level of erythropoietin (Epo) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Various proinflammatory cytokines have been tested for their action on the synthesis of Epo. Interleukin 1 (IL-1) and tumor necrosis factor-alpha(TNF-alpha) suppress Epo gene expression in isolated perfused rat kidneys and in human hepatoma cell cultures. IL-6 inhibits in the kidney, and conflicting results have been reported for its effect on Epo synthesis in hepatic cells. Several other cytokines tested were without effect. Thus, mainly IL-1 and TNF-alpha seem to be responsible for the defect in Epo production in severe systemic and renal inflammatory diseases.     

Dialysis in the treatment of renal failure in patients with liver disease

The value and effects of treating renal failure by dialysis are analyzed in a series of 84 patients with various types of liver disease. Although none of the 25 patients with cirrhosis survived, six of 50 with fulminant hepatic failure recovered completely as did seven of nine patients with renal failure secondary to extrahepatic biliary tract obstruction or with liver and renal damage following episodes of severe hypotension. Dialysis was required for seven weeks before diuresis occurred in one patient in the latter group. Both peritoneal and hemodialysis satisfactorily controlled plasma urea and creatinine levels, except in patients with fulminant hepatic failure in whom this was only achieved by hemodialysis. Complications of dialysis were most common in patients with cirrhosis and fulminant hepatic failure and included hypotension, gastrointestinal bleeding, and intraperitoneal sepsis. Overall, the results show that dialysis is only worth attempting in those patients in whom recovery of the underlying liver lesion is possible, and even then treatment for prolonged periods may be necessary.     

Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B

We have investigated the effect of N-acetylcysteine on hemodynamic variables, oxygen delivery (DO2), oxygen consumption (VO2), and oxygen extraction in patients with fulminant hepatic failure using independent methods of determining DO2 and VO2, thereby eliminating the effect of mathematical coupling, which may have biased previous studies. In 11 patients with severe fulminant hepatic failure, we documented the hemodynamic effects of N-acetylcysteine during the first 5 hours of a standard infusion regime and simultaneously measured VO2 using a method based on respiratory gas analysis. We related physiological changes to plasma N-acetylcysteine concentrations, and compared this group with 7 patients who received placebo infusions. A variable hemodynamic response to N-acetylcysteine was observed that did not differ significantly in comparison with the placebo group, and did not correlate with plasma drug concentrations. The most significant relationship observed between DO2 and VO2 in any patient predicted a 13-mL x min(-1) x m(-2) increase in VO2 when DO2 increased by 100 mL x min(-1) x m(-2); in 8 patients, VO2 was independent of DO2 over the range observed. In the group that received N-acetylcysteine, a small (mean 6 [SD 6] mL x min(-1) x m[-2]) increase in VO2 occurred in comparison with baseline after 1 hour of infusion (P < .01), but changes were not significantly different from the placebo group and were not sustained. N-Acetylcysteine infusion did not increase oxygen extraction or result in an improvement in whole-blood lactate levels or base excess during the study period. We conclude that N-acetylcysteine infusion does not result in clinically relevant improvements in global VO2, or in clinical markers of tissue hypoxia in patients with severe fulminant hepatic failure.     

Balance of inflammatory cytokines related to severity and mortality of murine sepsis

We tested the hypothesis that, during sepsis, the balance of pro- and anti-inflammatory cytokines is related to severity and survival. Cecal ligation and puncture (CLP) with a large (18-gauge)-, intermediate (21-gauge)-, or small (26-gauge)-diameter needle, or sham laparotomy, was performed on outbred CD-1 mice. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and the anti-inflammatory cytokine IL-10 were measured (by enzyme-linked immunosorbent assay) in serum, peritoneal lavage fluid, and liver and lung samples at 4, 8, 24, 48, and 96 h. As the diameter of the CLP needle decreased, the mortality rate decreased (at 48 h: large, 80%; intermediate, 40%; small, 20%; P < 0.05), the TNF-alpha and IL-6 concentrations decreased, and the time-to-peak TNF-alpha expression increased. In contrast, IL-10 concentration increased compared with baseline (serum at 24 h: large, 2.3-fold +/- 1.6-fold; intermediate, 2.0-fold +/- 0.5-fold; small, 49.9-fold +/- 8.3-fold; P < 0.05). Administration of IL-10 (5 microg, intraperitoneal) prior to CLP decreased mortality (P < 0.001). Administration of polyclonal anti-IL-10 serum prior to CLP (0.5 ml intraperitoneal) had the opposite effect and increased mortality (P < 0.001) and TNF-alpha, IL-6, and TNF-alpha mRNA expression compared with controls. Thus, severe sepsis is associated with a largely unopposed inflammatory response, and a largely unopposed inflammatory response (with anti-IL-10) results in severe sepsis and death. Less severe sepsis is associated with greater anti-inflammatory mediator expression, and greater anti-inflammatory mediator expression (with IL-10) results in less severe sepsis. Thus, the balance of inflammatory mediators is related to the severity and mortality of murine sepsis.     

Association of mutations in the core promoter and precore region of hepatitis virus with fulminant and severe acute hepatitis in Japan

It was recently reported that mutations in the precore and core promoter region of hepatitis B virus (HBV) are associated with fulminant hepatitis. The aim of this study was to investigate the association of mutations in the precore and core promoter region of HBV with fulminant and severe acute hepatitis. We studied Japanese patients with acute HBV infection, including seven patients with fulminant hepatitis, 12 with severe acute hepatitis and 41 with acute self-limited hepatitis. The presence of HBV mutants was examined by using a point mutation assay to detect a G to A transition at position 1896 in the precore region and an A to T transition at position 1762 and a G to A transition at position 1764 in the core promoter region. Significant differences in the proportion of mutations in the precore or core promoter region were present between patients with fulminant hepatitis and self-limited acute hepatitis (7/7 (100%) vs 4/41 (9.8%), P<0.01) and between severe acute hepatitis and self-limited acute hepatitis (6/12 (50.0%) vs 4/41 (9.8%), P<0.01). The frequency of mutation increased proportionately with the severity of disease in patients with acute HBV infection. Fulminant hepatitis B in Japan is closely associated with mutations in the core promoter and precore gene of HBV. Point mutation assays for HBV precore and core promoter analysis may be useful to predict the outcome of liver disease in patients with acute HBV infection.     

Reprioritization of liver protein synthesis resulting from recombinant human growth hormone supplementation in parenterally fed trauma patients: the effect of growth hormone on the acute-phase response

BACKGROUND: One of the major components of the metabolic response to severe trauma is the alteration in concentrations of a large number of plasma proteins referred to as acute-phase proteins (APP). The principle mediators of these liver-synthesized APP are mainly the cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). METHODS: We have measured the plasma levels of IL-6, TNF alpha, and 20 APP in 24 adult, severely injured, hypermetabolic and highly catabolic patients with multiple injuries within 48-60 hours after injury, when they were receiving maintenance fluids without calories or nitrogen, and subsequently during 7 days of total parenteral nutrition with (n = 12) or without (n = 12) recombinant human growth hormone supplementation (rhGH, 0.15 mg/kg/d). RESULTS: Baseline positive APP due to severe trauma include C-reactive protein (CRP), alpha-1 antichymotrypsin, alpha-1 acid glycoprotein, alpha-1 antitrypsin, fibronectin, and factor B. Negative APP include IgG, IgM, complement-3, prealbumin, transferrin, ceruloplasmin, and albumin. Except for CRP, alpha-1 antichymotrypsin, and albumin, all the APP levels increase during 7 days of nutritional support. Plasma levels of cytokines IL-6 and TNF-alpha, although initially markedly increased after injury, decrease with parenteral refeeding. There is a linear correlation between CRP and IL-6 levels and also between the transport proteins prealbumin and transferrin. Trauma-induced increases in CRP and IL-6 levels decreased with nutrition alone, but did not change with rhGH supplementation. An immunosuppressed state of injury is evident from the decreased immunoglobulin levels (IgG, IgM, IgA) in the trauma patients. Total parenteral nutrition alone increases the immunoglobulin levels to normal. However, with adjuvant rhGH, only IgA levels are normalized. CONCLUSIONS: Adjuvant rhGH therapy does not attenuate the reprioritization of acute liver protein synthesis and results in only limited restoration of host defenses. The clinical implications of these findings await further study.     

Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients

Plasma endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 1 receptor antagonist (IL-1ra), and interleukin 6 (IL-6) concentrations in 69 bacteremic patients were compared with those in 54 nonbacteremic patients suffering from suspected bacterial infections. Only three (11%) of the 27 patients with gram-negative bacteremia showed detectable levels of endotoxin. TNF-alpha was detected in 6% of the bacteremic patients and in none of the nonbacteremic patients. Median IL-6 levels were significantly higher in bacteremic than in nonbacteremic patients (55 vs. 0 pg/ml, p = 0.0008). IL-6 concentrations were similar in neutropenic and non-neutropenic bacteremic patients (median 55 vs. 74 pg/ml). In contrast, neutropenic bacteremic patients had significantly lower concentrations of IL-1ra than non-neutropenic bacteremic patients (250 vs. 1,950 pg/ml, p < 0.0001). Patients with fatal bacteremia had significantly higher concentrations of IL-6 and IL-1ra than the survivors (median, 450 vs. 40, p = 0.012 and 7,600 vs. 420 pg/ml, p = 0.0075, respectively). Determinations of endotoxin or TNF-alpha in patients with suspected bacteremia failed to offer clinically relevant data on the prognosis of these patients. IL-6 levels correlated with both the presence of bacteremia and the risk of death. Granulocytopenic patients with bacteremia had lower levels of circulating IL-1ra than patients with normal granulocyte counts, and these levels correlated with poor outcome.     

TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity

The pro-inflammatory cytokines IL-1 and TNF-alpha are primary mediators of the acute phase response, the complex reaction of the mammalian organism to infection and injury. Among the genes activated by TNF-alpha and IL-1 in a variety of cells is TNF-stimulated gene 6 (TSG-6). The TSG-6 cDNA encodes a secreted 35 kDa glycoprotein which is abundant in synovial fluids of patients with various forms of arthritis and detectable in serum of patients with different inflammatory or autoimmune disorders. TSG-6 protein consists of two structural domains: a hyaluronan-binding link module, the characteristic domain of the hyaladherin family of proteins, and a C-terminal CUB domain, present in a variety of diverse proteins. TSG-6 forms a stable complex with components of the plasma protein inter-alpha-inhibitor (I[alpha]I), a Kunitz-type serine protease inhibitor. TSG-6 and I(alpha)I synergize to inhibit plasmin, a serine protease involved in the activation of matrix metalloproteinases which are part of the proteolytic cascade associated with inflammation. Recombinant human TSG-6 protein exerts a potent anti-inflammatory effect in a murine model of acute inflammation. Modulation of the proteolytic network associated with inflammatory processes may be a mechanism whereby TSG-6, in cooperation with I(alpha)I, inhibits inflammation. Activation of the TSG-6 gene by pro-inflammatory cytokines, presence of TSG-6 protein in inflammatory lesions and its anti-inflammatory effect suggest a role for TSG-6 in a negative feed-back control of the inflammatory response.