Influenza interaction with cocirculating pathogens and its impact on surveillance, pathogenesis, and epidemic profile: A key role for mathematical modelling

International audienceEvidence is mounting that influenza virus interacts with other pathogens colonising or infecting the human respiratory tract. Taking into account interactions with other pathogens may be critical to determining the real influenza burden and the full impact of public health policies targeting influenza. This is particularly true for mathematical modelling studies, which have become critical in public health decision-making. Yet models usually focus on influenza virus acquisition and infection alone, thereby making broad oversimplifications of pathogen ecology. Herein, we report evidence of influenza virus interactions with bacteria and viruses and systematically review the modelling studies that have incorporated interactions. Despite the many studies examining possible associations between influenza and Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Neisseria meningitidis, respiratory syncytial virus (RSV), human rhinoviruses, human parainfluenza viruses, etc., very few mathematical models have integrated other pathogens alongside influenza. The notable exception is the pneumococcus-influenza interaction, for which several recent modelling studies demonstrate the power of dynamic modelling as an approach to test biological hypotheses on interaction mechanisms and estimate the strength of those interactions. We explore how different interference mechanisms may lead to unexpected incidence trends and possible misinterpretation, and we illustrate the impact of interactions on public health surveillance using simple transmission models. We demonstrate that the development of multipathogen models is essential to assessing the true public health burden of influenza and that it is needed to help improve planning and evaluation of control measures. Finally, we identify the public health, surveillance, modelling, and biological challenges and propose avenues of research for the coming years

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients