38 There are important issues with the statistical methods used to gauge the associations, other studies10 and 38 have found, as we have, that the different methods produce variable results. Moreover, negative binomial regression requires assumptions to be made about the data; Cabozantinib in vivo the observations should be independent and the virulence of the viruses should remain constant. The possible mechanisms underlying the interaction between S. pneumoniae and influenza and RSV have been reviewed by Bosch et al. 39 A primary host defence to infection is the secretion of a mucus layer

in the upper respiratory tract. Bacteria bind to the mucus 40 and 41 enabling them to be cleared by the action of cilia cells. However, primary viral infection destroys these epithelial cells through metabolic exhaustion or lysis 39 reducing mucus and bacterial clearance. 42 This enables bacteria to progress further into the respiratory

tract by inhalation or adherence to exposed cell surface receptors. 43 and 44 Viral factors produced by influenza and RSV also increase bacterial adherence. Influenza produces neuraminidase (NA), which cleaves sialic acids exposing bacterial receptors and thus increasing adherence. 45 RSV expresses RSV-protein G which acts directly as a bacterial receptor. 46 Viral infection may alter behaviour of the immune system, by modifying the expression of antimicrobial peptides 47 and adhesion proteins, these act as receptors for immune cells, however S. pneumoniae and other bacteria have been mTOR inhibitor shown to adhere to MTMR9 these proteins as well. 48 and 49 Influenza virus is also known to impair neutrophil function and increase apoptosis, 50 decrease oxidative burst 51 and reduce production and activity

of cytokines. 39 The time period of our analysis covers only seasonal influenza and excludes the H1N1 ‘swine flu’ pandemic. We censored our dataset at the week preceding the World Health Organization’s (WHO) declaration of the pandemic on 11th June 2009 because the UK surveillance systems were modified and enhanced during the pandemic, making direct comparisons with previous time periods difficult. During the second wave of the pandemic in winter 2010/2011, linkage between influenza and invasive bacterial infection surveillance reports suggested that between 6 and 11% (depending on age, with the highest percentage in the 15–44 year age group) of IPD cases had concurrent influenza.52 This is broadly consistent with our findings. We suggest that there is a small, but measurable association between IPD and RSV and influenza. These results are relevant for public health policy decision making. Prevention of viral respiratory infections may offer some additional benefit in terms of reducing invasive pneumococcal infections53 and prevention of pneumococcal infections during, say, influenza pandemics could see a reduction in hospitalizations and mortality.