Nina Buchtele

Chikungunya vaccines in development

ABSTRACT Chikungunya virus has become a global health threat, spreading to the industrial world of Europe and the Americas; no treatment or prophylactic vaccine is available. Since the late 1960s much effort has been put into the development of a vaccine, and several heterogeneous strategies have already been explored. Only two candidates have recently qualified to enter clinical phase II trials, a chikungunya virus-like particle-based vaccine and a recombinant live attenuated measles virus-vectored vaccine. This review focuses on the current status of vaccine development against chikungunya virus in humans and discusses the diversity of immunization strategies, results of recent human trials and promising vaccine candidates.

Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial

BACKGROUND Staphylococcal toxic shock syndrome is a superantigen-driven potentially life-threatening disease affecting mainly young and otherwise healthy individuals. Currently, no specific treatment or preventive measure is available. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers. METHODS In this randomised, double-blind, adjuvant-controlled, dose-escalation first-in-human trial, healthy adults aged 18-64 years were enrolled from the Medical University of Vienna, Austria. Participants were randomly assigned (2:1 and 3:1) by block randomisation (block sizes of three and 12) to receive increasing doses of rTSST-1v (100 ng to 30 μg) or the adjuvant comparator aluminium hydroxide (Al(OH)3) (200 μg, 600 μg, or 1 mg). Investigators and participants were masked to group allocation. The per-protocol population received a booster immunisation 42 days after the first vaccination. The primary endpoint was safety and tolerability of rTSST-1v. The per-protocol population included all participants who had adhered to the study protocol without any major protocol deviations. The per-protocol population was the primary analysis population for immunogenicity. The trial is registered with EudraCT, number 2013-003716-50, and ClinicalTrials.gov, number NCT02340338. FINDINGS Between Aug 19, 2014, and April 14, 2015, 46 participants were enrolled (safety population), of whom three were assigned to cohort 1 (two to receive 100 ng rTSST-1v and one to receive 200 μg Al(OH)3), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 μg Al(OH)3), four to cohort 3 (three to receive 1 μg rTSST-1v and one to receive 1 mg Al(OH)3), 12 to cohort 4 (nine to receive 3 μg rTSST-1v and three to receive 1 mg Al(OH)3), 12 to cohort 5 (nine to receive 10 μg rTSST-1v and three to receive 1 mg Al(OH)3), and 12 to cohort 6 (nine to receive 300 μg rTSST-1v and three to receive 1 mg Al(OH)3). 45 participants (98%) were included in the per-protocol population. rTSST-1v had a good safety profile, and no vaccination-related severe or serious adverse events occurred. Adverse event rates were similar between participants who received rTSST-1v and those who received placebo (26 [76%] vs 10 [83%]; p=0·62) independent of pre-existing TSST-1 immunity. INTERPRETATION rTSST-1v was safe, well-tolerated, and immunogenic. This study represents an important step in vaccine development to prevent or treat a potentially lethal disease. FUNDING Biomedizinische Forschungs GmbH.

D-dimer and histamine in early stage bacteremia: A prospective controlled cohort study

INTRODUCTION Plasma histamine levels and D-dimer predict disease severity and mortality in advanced septic shock. We hypothesized that increased plasma histamine levels parallel coagulation activation and yield prognostic significance already at a very early stage of bacteremia. PATIENTS AND METHODS This prospective controlled cohort study enrolled 72 consecutive non-surgical non-ICU-ward inpatients with newly culture-diagnosed bacteremia and a Pitt Bacteremia score ≤2 to determine the extent of histamine and D-dimer release and their predictive role on outcome at the earliest stage of blood stream infection. Age-matched healthy adults served as internal controls (n=36). A binominal logistic regression and a Cox proportional hazards regression analysis were performed to ascertain the effects of D-dimer and histamine on in-hospital mortality. RESULTS In contrast to plasma histamine, D-dimer levels were significantly higher within hours of culture-proven bacteremia. In-hospital mortality occurred in 17%. Histamine levels were neither associated with D-dimer level (r=0.04; p>0.05) nor with ICU admissions (r=0.06; p>0.05) and outcome (crude OR 0.8, 95% CI 0.3-1.9; p=0.6). In contrast, early-elevated D-dimer levels predicted mortality: the odds to die increased with the D-dimer level, and was 12.6 (crude OR, 95% CI 3-52; p=0.001) in patients with a D-dimer ≥4μg/mL (n=13). CONCLUSION Histamine levels are elevated in only few patients (4%) with newly diagnosed bacteremia. Our findings suggest that D-dimer, but not plasma histamine, could be a promising marker of lethality already at a very early stage of blood stream infection.

Successful weaning from 65-day extracorporeal membrane oxygenation therapy in influenza-associated acute respiratory distress syndrome

Introduction Data on prolonged extracorporeal membrane oxygenation (ECMO) usage in influenza associated acute respiratory distress syndrome (ARDS) are lacking. Furthermore, no consensus exists on when to terminate ECMO treatment in refractory cases. This report highlights additional treatment measures and complications in prolonged ECMO therapy and discusses associated ethical burdens. Case report We report on a 64-year-old man with confirmed H1N1 influenza virus infection who was successfully weaned from 65-day ECMO treatment with an excellent outcome. Conclusions Our experience suggests that prolonged ECMO therapy may be provided as long as only 1-organ failure exists and no lung fibrosis occurs. Active physical therapy, facilitated by ECMO treatment, is crucial and should be performed as early as possible.

Inhibition of Protease-Activated Receptor (PAR1) Reduces Activation of the Endothelium, Coagulation, Fibrinolysis and Inflammation during Human Endotoxemia

The protease-activated receptor-1 (PAR-1) is critically involved in the co-activation of coagulation and inflammatory responses. Vorapaxar is a reversible, orally active, low molecular weight, competitive antagonist of PAR-1.We investigated the effects of PAR-1 inhibition by vorapaxar on the inflammatory response, the activation of coagulation, fibrinolysis and endothelium during experimental endotoxemia. In this randomized, double blind, crossover trial, 16 healthy volunteers received a bolus infusion of 2 ng/kg lipopolysaccharide (LPS) ± placebo/vorapaxar with a washout period of 8 weeks. Vorapaxar dosing was guided by thrombin receptor-activating peptide-6-induced whole blood aggregometry. Participants received 10 mg vorapaxar or placebo as an initial dose and, depending on the aggregometry, potentially an additional 10 mg. Goal was > 80% inhibition of aggregation compared with baseline. Vorapaxar significantly reduced the LPS-induced increase in pro-thrombin fragments F1 + 2 by a median of 27% (quartiles: 11-49%), thrombin-anti-thrombin concentrations by 22% (-3 to 46%) and plasmin-anti-plasmin levels by 38% (23-53%). PAR-1 inhibition dampened peak concentrations of tumour necrosis factor -α, interleukin-6 and consequently C-reactive protein by 66% (-11-71%), 50% (15-79%) and 23% (16-38%), respectively. Vorapaxar decreased maximum von Willebrand factor levels by 29% (26-51%) and soluble E-selectin concentrations by 30% (25-38%) after LPS infusion. PAR-1 inhibition did not affect thrombomodulin, soluble P-selectin and platelet factor-4 concentrations.PAR-1 inhibition significantly reduced the activation of coagulation, fibrinolysis, the inflammatory response and endothelial activation during experimental human endotoxemia.

Prognosis of overt disseminated intravascular coagulation in patients admitted to a medical emergency department

Objective To assess the prevalence, characteristics and prognosis of overt disseminated intravascular coagulation (DIC) in adult emergency department (ED) patients and identify markers of poor outcome. Materials and methods In a chart review study, we analysed the occurrence of overt DIC in all patients (n=1 001 727) attending the University’s ED from 2003 to 2014 applying the ISTH DIC score. The primary outcome measure was 30-day mortality. Logistic regression analysis was used to determine predictors of mortality. Results The initial inter-rater reliability in the diagnosis of DIC was 0.85 [&kgr;; 95% confidence interval (CI), 0.77–0.92]. The main DIC precipitators were malignancy (47%), cardiovascular diseases (CVD, 27%) and sepsis (16%). Hyperfibrinolytic DIC occurred in 27% of patients and was over-represented in those with cardiac arrest (68%). Thirty-day mortality (52%) was inversely associated with fibrinogen levels on admission [adjusted odds ratio, 0.49; 95% CI: 0.30–0.82; P=0.006]. Afibrinogenaemia implied an even 10-fold increased risk of dying (crude odds ratio, 10.0; 95% CI: 3.2–31.4; P<0.001). D-dimer and platelet count had no predictive value. Appropriate ICD-10 coding for DIC was present in only 1.8% of cases. Conclusion Overt DIC is a rare but underdiagnosed event in ED patients. In this collective, cardiac arrest is a dominant cause of DIC presenting with a fibrinolytic phenotype. The degree of hypofibrinogenaemia on admission strongly and linearly predicted early death.

Dexamethasone inhibits endotoxin-induced coagulopathy in human lungs.

Essentials Glucocorticoids are associated with an increased risk of thrombosis. Healthy volunteers received dexamethasone or placebo in an endotoxin lung instillation model. Dexamethasone suppressed thrombin generation in bronchoalveolar lavage. Glucocorticoids inhibit endotoxin induced pulmonary coagulopathy.

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification.

Added value of the DIC score and of D-dimer to predict outcome after successfully resuscitated out-of-hospital cardiac arrest

BACKGROUND Recent Korean data suggest a high prevalence of overt disseminated intravascular coagulation (DIC) and a good predictive performance of the ISTH DIC score in successfully resuscitated out-of-hospital cardiac arrest. OBJECTIVES We hypothesised that in a European cohort of resuscitated out-of-hospital cardiac arrest patients the prevalence of DIC is substantially lower. Furthermore, the determination of D-dimer levels at admission, but not the DIC score, could improve mortality prediction above traditional predictors. PATIENTS/METHODS Data were extracted from a prospective cardiac arrest registry including patients admitted between 2006 and 2015, who achieved return of spontaneous circulation and had parameters for DIC score calculation available. The primary outcome was the prevalence of overt DIC at admission. Secondary outcomes included the association of overt DIC with 30-day mortality and the contribution of the DIC score and D-dimer levels to 30-day mortality prediction using logistic regression. Three stepwise models were evaluated by receiver-operating-characteristic analysis. RESULTS Out of 1179 patients 388 were included in the study. Overt DIC was present in 8% of patients and associated with substantial 30-day mortality (83% vs. 39%). The AUC for model 1, including traditional mortality predictors, was 0.83. The inclusion of D-dimer levels significantly improved prognostication above traditional predictors (model 3, AUC 0.89), whereas the inclusion of the DIC Score had no effect on mortality prediction (model 2, AUC 0.83). CONCLUSION Overt DIC was rare in a European cohort of out-of-hospital cardiac arrest patients. D-dimer levels improved 30-day mortality prediction and provided added value to assess early mortality risk after successful resuscitation.

Angiotensin II for the treatment of vasodilatory shock: enough data to consider angiotensin II safe?

A recent structured review by Busse et al. confirmed the efficacy of angiotensin II in terms of increasing blood pressure in patients with different types of shock [1]. The majority of data for this analysis came from the recently published ATHOS-3 trial which showed that angiotensin II effectively increased blood pressure in patients with vasodilatory shock receiving high-dose vasopressors [2]. In this trial, safety was defined as the secondary outcome. Considering the similar total number of adverse events in both groups, the administration of angiotensin II seemed safe. Antonucci et al. had already raised some caution about the administration of angiotensin II [3]. In addition, we want to add some further comments about the use of angiotensin II, especially as it has recently been approved by the US Food and Drug administration. Taking a closer look at the subgroups of adverse events, patients in the treatment group were significantly more likely to develop infection or delirium. High doses of vasopressors are known to cause mesenteric ischemia [4], which may impair intestinal mucosal barrier function resulting in transmission of enteric bacteria into the bloodstream. It would be of great interest to analyse these specific adverse events in another structured review or meta-analysis. Furthermore, the significant decrease in the cardiovascular Sequential Organ Failure Assessment (SOFA) score in the treatment group must be interpreted cautiously. The infusion of angiotensin II probably allowed a decrease in background catecholamines and therefore a decrease in the cardiovascular SOFA score. The SOFA score accurately predicts mortality of critically ill patients, but the cardiovascular domain has its limitations [5]. It is unclear whether the cardiovascular component of the SOFA score can be used if vasopressors other than catecholamines are infused. The key issue is whether additional points for equivalent doses of angiotensin have to be included in the score. Although hypotension improved, the total score worsened to a similar extent in both groups, suggesting that functions of other organ systems may have deteriorated. It seems that finally efforts in developing a new effective substance in refractory shock have paid off, but the safety results have to be treated with caution.