Global seasonality of respiratory viruses and the association between viral acute respiratory infection and subsequent pneumococcal disease

Abstract

Introduction Influenza virus (IFV), respiratory syncytial virus (RSV), parainfluenza virus (PIV), and metapneumovirus (MPV) are the most common viruses associated with acute lower respiratory infections in young children and the elderly. A global report of seasonality of these viruses is needed to inform public health strategies and programmes for their control. The association between viral infection and subsequent pneumococcal disease has been long recognised but the existing studies report inconsistent findings, possibly due to a variety of methodological challenges in these studies. This thesis aims to understand global seasonality of IFV, RSV, PIV, and MPV, and to understand the role of RSV seasonality on lower and middle income countries (LMICs) planning of introduction of RSV prevention strategies. This thesis also aims to understand the existing evidence regarding the association between viral infection and pneumococcal disease as the first step, and as the second step, to assess the association using Scottish health data. Methods Laboratory-confirmed viral activity data were collected from systematic literature searches, public datasets, and research datasets shared by collaborators in RSV Global Epidemiology Network (RSV GEN). Monthly annual average percentage (AAP) was calculated for each site as the relative strength of virus activity. Duration of seasonal epidemics were defined as the minimum number of months to account for 75% of annual positive samples. Based on monthly AAP, IFV and RSV activity was modelled using sitespecific temperature and relative humidity data. A prediction tool was used to help estimate local seasonal epidemics of IFV and RSV. Using RSV seasonality data in LMICs, the effectiveness and efficiency of different candidate approaches of RSV immunisation was compared. A separate systematic review was conducted to critically appraise the methodologies and findings of existing population studies on the association between viral infection and subsequent pneumococcal disease. Based on the findings of this review, an ecological study was conducted using laboratory-confirmed viral and pneumococcal data to assess the association. The attributable percentage of invasive pneumococcal disease to IFV, RSV, PIV, and MPV was estimated in all ages, <6y, 6–64y, and >64y. Results IFV had clear seasonal epidemics in winter months in most temperate sites but the timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike IFV, RSV had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. PIV epidemics were found mostly in spring and early summer months in each hemisphere. MPV epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. The prediction model had good predictability of the local average epidemic months of IFV and RSV. RSV seasonality was distinct and was relatively stable over several years in most LMICs. Compared with a year-round approach, seasonal approaches were more supported in LMICs with clear seasonality. The systematic review of viral-pneumococcal association studies found that failure to account for shared seasonal factors between viral and pneumococcal infection was common and that the association was likely to differ by virus type, highlighting the needs for viral-specific analysis. Using laboratory-confirmed viral and pneumococcal data in Scotland, IFV and RSV were found to be associated with subsequent invasive pneumococcal pneumonia across all age groups. Conclusion This is the first study to provide global representations of month-by-month activity of IFV, RSV, PIV and MPV. The prediction model is helpful in predicting the local onset of IFV and RSV epidemics. The seasonality information presented in the thesis has important implications for health services planning, the timing of RSV passive prophylaxis and the strategy of IFV and future RSV vaccination. A seasonal approach of RSV immunisation can be considered for most LMICs with clear RSV seasonality. The viral-pneumococcal association study finds a consistent support for the association between IFV and RSV in all age groups. Future individual-patient-level studies are warranted to confirm the findings.