Use of neuraminidase inhibitors in primary health care during pandemic and seasonal influenza between 2009 and 2013: Outpatient influenza antiviral treatment

International audienceBACKGROUND:In a context of controversy about influenza antiviral treatments, this study assessed primary health-care physicians' prescription of neuraminidase inhibitors (NIs) in France during pandemic and seasonal influenza between 2009 and 2013.METHODS:This observational study, using data recorded in three national databases, estimated the rate of NI prescription among influenza-like illness (ILI) patients seen in GP and paediatrician consultations, and determined factors associated with this prescription according to a multivariate analysis. NI delivery by pharmacists was also evaluated.RESULTS:Rates of NI prescription were estimated to be 61.1% among ILI patients with a severe influenza risk factor seen in GP consultation during the A(H1N1)pdm2009 pandemic versus an average rate of 25.9% during the three following seasonal influenza epidemics. Factors associated with NI prescription were a chronic disease in patients under 65 years (OR 14.85; 95% CI 13.00, 16.97) and in those aged 65 and older (OR 7.54; 5.86, 9.70), an age ≥65 years in patients without chronic disease (OR 1.35; 1.04, 1.74), a pregnancy (OR 10.63; 7.67, 15.76), obesity (OR 4.67; 3.50, 6.22) and a consultation during the pandemic A(H1N1)pdm2009 (OR 3.19; 2.93, 3.48). The number of antiviral treatments delivered by pharmacists during the A(H1N1)pdm2009 pandemic was 835 per 100,000 inhabitants, and an average of 275 per 100,000 inhabitants during the three following seasonal influenza epidemics.CONCLUSIONS:Although physicians seem to follow the recommended indications for NIs in primary health-care practice, this study confirms the low rate of NI prescription to ILI patients with a severe influenza risk factor, especially during seasonal epidemics

I-MOVE multicentre case–control study 2010/11 to 2014/15 : is there within-season waning of influenza type/subtype vaccine effectiveness with increasing time since vaccination?

Influenza vaccines are currently the best method available to prevent seasonal influenza infection. In most European countries one dose (or two doses for children) of seasonal vaccine is given from September to December to the elderly and other target groups for vaccination. In Europe, influenza seasons can last until mid-May (1), and it is expected that vaccination conveys protection on the individual for the duration of the season. In 13/15 reviewed studies on the length of vaccine-induced protection among the elderly, using anti-haemagglutination antibody titres as a proxy for seroprotection levels, seroprotection rates lasted at least >4 months after vaccination (2). However in the 2011-12 influenza season various studies in Europe reported a decrease in influenza vaccine effectiveness (VE) against A(H3N2) over time within the season (3–5). In the United States, a decrease in VE against A(H3N2) with time since vaccination was suggested in the 2007-8 influenza season (6). The observed decrease of VE over time can be explained by viral change (notably antigenic drift) occurring in the season. Drift in B viruses may be slower than in A viruses (7), and A(H3N2) viruses undergo antigenic drift more frequently than A(H1N1)pdm09 viruses (8). The decrease of VE over time can also be explained by a waning of the immunity conferred by the vaccine independently from viral changes. If vaccine-induced protection wanes more rapidly during the season, then depending on the start and duration of the influenza season, the decline of VE may cause increases in overall incidence, hospitalisations and deaths. Changes to vaccination strategies (timing and boosters) may be needed. As anti-haemagglutination antibody titres are not well defined as a correlate of protection (9,10), vaccine efficacy (as measured in trials) or vaccine effectiveness observational studies may be one way to measure vaccine-induced protection. These studies require a large sample size to model VE by time since vaccination and currently, most of the seasonal observational studies lack the precision required to provide evidence for waning immunity. In this study we pooled data across five post-pandemic seasons (2010/11-2014/15) from the I-MOVE (Influenza - Monitoring Vaccine Effectiveness) multicentre case control studies (1,3,11,12), to obtain a greater sample size to study the effects of time since vaccination on influenza type/subtype-specific VE. We measure influenza type/subtype-specific VE by time since vaccination for the overall season, but also in the early influenza phase; under the hypothesis that virological changes are fewer in the early season, but waning of the vaccine effect should be present regardless of time within the influenza phase

I-MOVE Multi-Centre Case Control Study 2010-11: Overall and Stratified Estimates of Influenza Vaccine Effectiveness in Europe

BACKGROUND: In the third season of I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe), we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in eight European Union (EU) member states to estimate 2010/11 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. METHODS: Using systematic sampling, practitioners swabbed ILI/ARI patients within seven days of symptom onset. We compared influenza-positive to influenza laboratory-negative patients among those meeting the EU ILI case definition. A valid vaccination corresponded to > 14 days between receiving a dose of vaccine and symptom onset. We used multiple imputation with chained equations to estimate missing values. Using logistic regression with study as fixed effect we calculated influenza VE adjusting for potential confounders. We estimated influenza VE overall, by influenza type, age group and among the target group for vaccination. RESULTS: We included 2019 cases and 2391 controls in the analysis. Adjusted VE was 52% (95% CI 30-67) overall (N = 4410), 55% (95% CI 29-72) against A(H1N1) and 50% (95% CI 14-71) against influenza B. Adjusted VE against all influenza subtypes was 66% (95% CI 15-86), 41% (95% CI -3-66) and 60% (95% CI 17-81) among those aged 0-14, 15-59 and ≥60 respectively. Among target groups for vaccination (N = 1004), VE was 56% (95% CI 34-71) overall, 59% (95% CI 32-75) against A(H1N1) and 63% (95% CI 31-81) against influenza B. CONCLUSIONS: Results suggest moderate protection from 2010-11 trivalent influenza vaccines against medically-attended ILI laboratory-confirmed as influenza across Europe. Adjusted and stratified influenza VE estimates are possible with the large sample size of this multi-centre case-control. I-MOVE shows how a network can provide precise summary VE measures across Europe

Caffeine reduces TNFalpha up-regulation in human adipose tissue primary culture.

International audienceAdipose tissue secretions play an important role in the development of obesity-related pathologies such as diabetes. Through inflammatory cytokines production, adipose tissue stromavascular fraction cells (SVF), and essentially macrophages, promote adipocyte insulin resistance by a paracrine way. Since xanthine family compounds such as caffeine were shown to decrease inflammatory production by human blood cells, we investigated the possible effect of caffeine on Tumor Necrosis Factor alpha (TNFalpha) and Interleukin-6 (IL-6) expression by human adipose tissue primary culture. For that purpose, human subcutaneous adipose tissue obtained from healthy non-obese women (BMI: 26.7 +/- 2.2 kg/m2) after abdominal dermolipectomy, was split into explants and cultured for 6 hours with or without caffeine. Three different concentrations of caffeine were tested (0.5 microg/mL, 5 microg/mL and 50 microg/mL). After 6 hours of treatment, explants were subjected to collagenase digestion in order to isolate adipocytes and SVF cells. Then, TNFalpha and IL-6 mRNA were analysed by real-time PCR alternatively in adipocytes and SVF cells. In parallel, we checked gene expression of markers involved in adipocyte differenciation and in SVF cells inflammation and proliferation. Our findings show a strong and dose dependent down-regulation of TNF-alpha gene expression in both adipocyte and SVF cells whereas IL-6 was only down regulated in SVF cells. No effect of caffeine was noticed on the other genes studied. Thus, caffeine, by decreasing TNFalpha expression, could improve adipose tissue inflammation during obesity

The transcriptional co-activator PGC-1alpha up regulates apelin in human and mouse adipocytes.

International audienceBy using pangenomic microarray, we identified apelin as a unique adipokine up regulated by the transcriptional co-activator peroxisome proliferator-activated receptor gamma (PPARgamma) co-activator 1alpha (PGC-1alpha) in human white adipocytes. We investigated its regulation in vitro and in vivo. Overexpression of PGC-1alpha by adenovirus in human adipocytes induces apelin expression and secretion. Pharmacological induction of cAMP, an upstream regulator of endogenous PGC-1alpha expression, up regulates apelin gene expression and also apelin secretion in human and mice adipocytes. Moreover, during cold exposure in mice, a physiological situation known to induce both cAMP and PGC-1alpha, apelin expression in adipocytes and plasma levels were increased. This is the first demonstration that PGC-1alpha is involved in the regulation of an adipokine gene expression and release

Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo.

International audienceApelin is a peptide present in different cell types and secreted by adipocytes in humans and rodents. Apelin exerts its effects through a G-protein coupled receptor called APJ. During the last years, a role of apelin/APJ in energy metabolism has emerged. Apelin was shown to stimulate glucose uptake in skeletal muscle through an AMP-activated protein kinase (AMPK)-dependent pathway in mice. So far, no metabolic effects of apelin have been reported on human adipose tissue (AT). Thus, the effect of apelin on AMPK in AT was measured as well as AMPK-mediated effects such as inhibition of lipolysis and stimulation of glucose uptake. AMPK and Acetyl-CoA Carboxylase phosphorylation were measured by western blot to reflect AMPK activity. Lipolysis and glucose uptake were measured, ex vivo, in response to apelin on isolated adipocytes and explants from AT of the subcutaneous region of healthy subjects (BMI: 25.6 ± 0.8 kg/m2, n = 30 in total). APJ mRNA and protein were present in human AT and isolated adipocytes. Apelin stimulated AMPK phosphorylation at Thr-172 in a dose-dependent manner in human AT which was associated to increased glucose uptake since, C Compound (20 μM), an AMPK inhibitor, completely prevented apelin-induced glucose uptake. However, in isolated adipocytes or AT explants, apelin had no significant effect on basal and isoprenaline-stimulated lipolysis. Thus, these results reveal, for the first time, that apelin is able to act on human AT in order to stimulate AMPK and glucose uptake

Effect of hypocaloric diet-induced weight loss in obese women on plasma apelin and adipose tissue expression of apelin and APJ.

International audienceOBJECTIVE: Apelin is a novel adipokine acting on APJ receptor, regulated by insulin and tumor necrosis factor-alpha (TNF-alpha) in adipose tissue (AT). Plasma apelin levels are increased in obese hyperinsulinemic subjects. The aim was to investigate whether the hypocaloric diet associated with weight loss modifies the elevated plasma apelin levels and the expression of apelin and APJ receptor in AT in obese women. DESIGN AND METHODS: Fasting plasma levels of apelin and TNF-alpha as well as mRNA levels of apelin and APJ in AT were measured before and after a 12-week hypocaloric weight-reducing diet in 20 obese women (body mass index (BMI) before diet 32.2+/-6.4 kg/m(2)). Twelve healthy women with a BMI of 20.7+/-0.6 kg/m(2) served as reference. RESULTS: Plasma levels of apelin and TNF-alpha were higher in obese compared with lean controls. The hypocaloric diet resulted in a significant decrease of BMI to 29.8+/-6.3 kg/m(2), plasma insulin (8.16+/-0.73 to 6.58+/-0.66 mU/l), apelin (369+/-25 pg/ml to 257+/-12 pg/ml), TNF-alpha levels (0.66+/-0.04 pg/ml to 0.56+/-0.04 pg/ml), and AT mRNAs of apelin and APJ. In addition, changes in AT mRNA apelin were related to changes in AT mRNA APJ levels. CONCLUSION: The hypocaloric diet associated with weight loss reduces the increased plasma and AT expression of apelin in obese women. This reduced apelin expression in AT could contribute to decreased circulating apelin levels