Hepatitis E and blood donation safety in selected European countries: a shift to screening?

The public health implications of hepatitis E virus (HEV) in Europe have changed due to increasing numbers of hepatitis E cases and recent reports of chronic, persistent HEV infections associated with progression to cirrhosis in immunosuppressed patients. The main infectious risk for such immunosuppressed patients is exposure to undercooked infected pork products and blood transfusion. We summarised the epidemiology of HEV infections among blood donors and also outlined any strategies to prevent transfusion-transmitted HEV, in 11 European countries. In response to the threat posed by HEV and related public and political concerns, most of the observed countries determined seroprevalence of HEV in donors and presence of HEV RNA in blood donations. France, Germany, Spain and the United Kingdom (UK) reported cases of transfusion-transmitted HEV. Ireland and the UK have already implemented HEV RNA screening of blood donations; the Netherlands will start in 2017. Germany and France perform screening for HEV RNA in several blood establishments or plasma donations intended for use in high-risk patients respectively and, with Switzerland, are considering implementing selective or universal screening nationwide. In Greece, Portugal, Italy and Spain, the blood authorities are evaluating the situation. Denmark decided not to implement the HEV screening of blood donations.

Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial.

BACKGROUND: In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload.In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. METHODS/DESIGN: This is a double blind, multicenter, placebo-controlled randomized trial.Cirrhotic patients with a prolonged INR (≥1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. DISCUSSION: Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study. TRIAL REGISTRATION: The trial is registered at http://www.trialregister.nl with number NTR3174. This registry is accepted by the ICMJE.

The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial.

BACKGROUND: Systemic inflammation in response to a femur fracture and the additional fixation is associated with inflammatory complications, such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. The injury itself, but also the additional procedure of femoral fixation induces a release of pro-inflammatory cytokines such as interleukin-6. This results in an aggravation of the initial systemic inflammatory response, and can cause an increased risk for the development of inflammatory complications. Recent studies have shown that administration of the serum protein C1-esterase inhibitor can significantly reduce the release of circulating pro-inflammatory cytokines in response to acute systemic inflammation. OBJECTIVE: Attenuation of the surgery-induced additional systemic inflammatory response by perioperative treatment with C1-esterase inhibitor of trauma patients with a femur fracture. METHODS: The study is designed as a double-blind randomized placebo-controlled trial. Trauma patients with a femur fracture, Injury Severity Score ≥ 18 and age 18-80 years are included after obtaining informed consent. They are randomized for administration of 200 U/kg C1-esterase inhibitor intravenously or placebo (saline 0.9%) just before the start of the procedure of femoral fixation. The primary endpoint of the study is Δ interleukin-6, measured at t = 0, just before start of the femur fixation surgery and administration of C1-esterase inhibitor, and t = 6, 6 hours after administration of C1-esterase inhibitor and the femur fixation. CONCLUSION: This study intents to identify C1-esterase inhibitor as a safe and potent anti-inflammatory agent, that is capable of suppressing systemic inflammation in trauma patients. This might facilitate early total care procedures by lowering the risk of inflammation in response to the surgical intervention. This could result in increased functional outcomes and reduced health care related costs.

C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia.

OBJECTIVE: Besides its role in regulation of the complement and contact system, C1-esterase inhibitor has other immunomodulating effects that could prove beneficial in patients with acute inflammation such as during sepsis or after trauma. We examined the immunomodulating properties of C1-esterase inhibitor during human experimental endotoxemia, in which the innate immune system is activated in the absence of activation of the classic complement pathway. DESIGN: Double-blind placebo-controlled study. SETTING: Research intensive care unit of the Radboud University Nijmegen Medical Centre. SUBJECTS: Twenty healthy volunteers. INTERVENTIONS: Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide. Thirty minutes thereafter (to prevent binding of lipopolysaccharide), C1-esterase inhibitor concentrate (100 U/kg, n = 10) or placebo (n = 10) was infused. MEASUREMENTS AND MAIN RESULTS: Pro- and anti-inflammatory mediators, markers of endothelial and complement activation, hemodynamics, body temperature, and symptoms were measured. C1-esterase inhibitor reduced the release of proinflammatory cytokines as well as C-reactive protein (peak levels of: interleukin-6 1521 ± 209 vs. 932 ± 174 pg/mL [p = .04], tumor necrosis factor-α 1213 ± 187 vs. 827 ± 167 pg/mL [p = .10], monocyte chemotactic protein-1 6161 ± 1302 vs. 3373 ± 228 pg/mL [p = .03], interleukin-1ß 34 ± 5 vs. 23 ± 2 pg/mL [p < .01], C-reactive protein 39 ± 4 vs. 29 ± 2 mg/L [p = .02]). In contrast, release of the anti-inflammatory cytokine interleukin-10 was increased by C1-esterase inhibitor (peak level 73 ± 11 vs. 121 ± 18 pg/mL, p = .02). The increase in interleukin-1 receptor antagonist tended to be smaller in the C1-esterase inhibitor group, but this effect did not reach statistical significance (p = .07). Markers for endothelial activation were increased after lipopolysaccharide infusion, but no significant differences between groups were observed. The lipopolysaccharide-induced changes in heart rate, blood pressure, body temperature, and symptoms (all p < .001 over time) were not influenced by C1-esterase inhibitor. Complement fragment C4 was not increased after lipopolysaccharide challenge. CONCLUSIONS: This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans.

Mannose-binding lectin (MBL) substitution: recovery of opsonic function in vivo lags behind MBL serum levels.

Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immunocompromised patients. MBL substitution in these patients might diminish these risks. We therefore performed an open, uncontrolled safety and pharmacokinetic MBL-substitution study in 12 pediatric oncology patients with chemotherapy-induced neutropenia. Twice weekly MBL infusions with plasma-derived MBL yielded MBL trough levels >1.0 microg/ml. We tested whether MBL substitution in vivo increased MBL-dependent complement activation and opsonophagocytosis of zymosan in vitro. Upon MBL substitution, opsonophagocytosis by control neutrophils increased significantly (p < 0.001) but remained suboptimal, although repeated MBL infusions resulted in improvement over time. The MBL-dependent MBL-associated serine protease (MASP)-mediated complement C3 and C4 activation also showed a suboptimal increase. To explain these results, complement activation was studied in detail. We found that in the presence of normal MASP-2 blood levels, MASP-2 activity (p < 0.0001) was reduced as well as the alternative pathway of complement activation (p < 0.05). This MBL-substitution study demonstrates that plasma-derived MBL infusions increase MBL/MASP-mediated C3 and C4 activation and opsonophagocytosis, but that higher circulating levels of plasma-derived MBL are required to achieve MBL-mediated complement activation comparable to healthy controls. Other patient cohorts should be considered to demonstrate clinical efficacy in phase II/III MBL-substitution studies, because we found a suboptimal recovery of (in vitro) biological activity upon MBL substitution in our neutropenic pediatric oncology cohort.

Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotherapy-induced neutropaenia.

Mannose-binding lectin (MBL)-deficient children with cancer may benefit from substitution of the innate immune protein MBL during chemotherapy-induced neutropaenia. We determined the safety and pharmacokinetics of MBL substitution in a phase II study in MBL-deficient children. Twelve MBL-deficient children with cancer (aged 0-12 years) received infusions of plasma-derived MBL once, or twice weekly during a chemotherapy-induced neutropaenic episode (range: 1-4 weeks). Four patients participated multiple times. Target levels of 1.0 microg/ml were considered therapeutic. In total, 65 MBL infusions were given. No MBL-related adverse reactions were observed, and the observed trough level was 1.06 microg/ml (range: 0.66-2.05 microg/ml). Pharmacokinetics were not related to age after correction for body weight. The half-life of MBL, for a child of 25 kg, was 36.4h (range: 23.7-66.6h). No anti-MBL antibodies were measured 4 weeks after each MBL course. Substitution therapy with MBL-SSI twice weekly was safe and resulted in trough levels considered protective.