tetano
Editor, Senior Moderator
Jake Dunning, Honorary Research Fellow
Centre for Respiratory Infection, Imperial College London, Norfolk Place, London W2 1PG
As an infectious diseases clinician and influenza researcher, I have been involved in the management of over 150 patients with severe flu since pandemic H1N1 influenza (pH1N1) emerged in 2009. Many of these patients required intensive care and some died. My personal experience of pH1N1 is not atypical: during the UK?s first post-pandemic winter (2010/11) there were 8,797 influenza hospitalisations in England alone. At the peak of the outbreak, 851 critical care beds (~20% of UK capacity) were occupied by patients with flu - mostly younger adults and children infected with pH1N1.[1] Despite the great number of hospitalisations and deaths from influenza, antivirals were prescribed infrequently prior to admission (<3%) in contrast to generous prescription of antibacterial drugs (25% in our series).[2] Severe pH1N1 infections continued to occur in 2013/14[3] and are expected to continue globally in the post-pandemic period.
The latest Cochrane review of neuraminidase inhibitors for influenza[4] was an impressive undertaking but unfortunately addressed the wrong question. It is unable to provide the answers we need. Consistent with their previous findings[5] the authors found that, in a randomised controlled trial (RCT) setting, oseltamivir and zanamivir modestly reduced the duration of symptoms in previously healthy individuals with uncomplicated illness caused by non-pandemic, seasonal influenza viruses. Importantly, their findings do not address antiviral effectiveness in severe influenza, or in illness caused by pH1N1, or in patients with risk factors for severe illness. Therefore, these new findings cannot guide decisions about future antiviral stockpiling or the treatment of severe flu.[6]
Those responsible for pandemic planning and response had to rely on seasonal flu RCT data to make decisions on stockpiling and licensing. We now have abundant fresh evidence from the 2009/10 pandemic, including a recent systematic review of 78 observational studies (containing data from >29,000 patients hospitalised during the 2009-10 pandemic). After careful adjustments for confounding effects, it was shown that antiviral therapy was associated with significant reductions in mortality in adults, most notably a 50% reduction with early treatment.[7]
The clear discrepancy between the Cochrane group?s conclusions and the extensive, global experience of antivirals suggests that something is amiss. Observational studies have limitations, but so do RCTs and systematic reviews. Observational studies are vulnerable to bias, but stringent systematic reviews of RCTs can be misleading if the findings are not interpreted in an appropriate context. Rather than focussing on RCT data alone, we need to be pragmatic when considering how to treat flu now and in the future, and when planning how to mitigate future, unpredictable pandemics. We will serve patients best by looking at - and scrutinising - all available data, while understanding and accepting the limitations of different methodologies.
If we ignore the full range of evidence we will be misled in our management. By only accepting the narrowest of definitions of acceptable evidence, we would deny patients effective treatments and endanger public health. I encourage the Cochrane Collaboration to engage with those who are developing clinical trial protocols ahead of future outbreaks and urge them to help identify sources of independent funding. Such forward planning may prevent further confusion arising for doctors and patients, but we also require balanced communication of evidence. Clinical trial data must be transparent and open, but this issue should not be conflated with the need for deployment of safe and effective antiviral drugs.
[1] Surveillance of influenza and other respiratory viruses in the UK: 2010-11 report, http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1296687414154 (2010).
[2] Dunning, J., et al. Use of antivirals and antibiotics in pandemic influenza: findings from the UK MOSAIC study. Presented at ISIRV Options for the Control of Influenza, Cape Town, South Africa. 5-10 Sept 2013.
[3] PHE Weekly National Influenza Report: 10 April 2014 - week 15 report (up to week 14 data), http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317141076205 (2014).
[4] Jefferson, T. et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 4, CD008965, doi:10.1002/14651858.CD008965.pub4 (2014).
[5] Jefferson, T., Jones, M., Doshi, P. & Del Mar, C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 339, b5106 (2009).
[6] Jefferson, T. & Doshi, P. Multisystem failure: the story of anti-influenza drugs. BMJ 348, g2263, doi:10.1136/bmj.g2263 (2014).
[7] Muthuri, S. G. et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data (early online publication). The Lancet Respiratory Medicine, doi:http://dx.doi.org/10.1016/S2213-2600(14)70041-4 (2014).
Competing interests: When giving talks on influenza, JD has received travel and accommodation expenses and/or registration fee waivers from the following conference/meeting organisers: European Society of Clinical Microbiology and Infectious Diseases; British HIV Association; British Thoracic Society; Public Health England; Royal Society of Medicine; International Severe Acute Respiratory and emerging Infection Consortium. JD received travel and accommodation expenses from Health Protection Agency for a pandemic secondment and from World Health Organization when serving as a technical consultant on influenza. JD has contributed to the development of local and national guidelines for the clinical management of influenza. JD is an investigator in the MOSAIC influenza study, funded by the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK.
http://www.bmj.com/content/348/bmj.g2263/rr/694966
Centre for Respiratory Infection, Imperial College London, Norfolk Place, London W2 1PG
As an infectious diseases clinician and influenza researcher, I have been involved in the management of over 150 patients with severe flu since pandemic H1N1 influenza (pH1N1) emerged in 2009. Many of these patients required intensive care and some died. My personal experience of pH1N1 is not atypical: during the UK?s first post-pandemic winter (2010/11) there were 8,797 influenza hospitalisations in England alone. At the peak of the outbreak, 851 critical care beds (~20% of UK capacity) were occupied by patients with flu - mostly younger adults and children infected with pH1N1.[1] Despite the great number of hospitalisations and deaths from influenza, antivirals were prescribed infrequently prior to admission (<3%) in contrast to generous prescription of antibacterial drugs (25% in our series).[2] Severe pH1N1 infections continued to occur in 2013/14[3] and are expected to continue globally in the post-pandemic period.
The latest Cochrane review of neuraminidase inhibitors for influenza[4] was an impressive undertaking but unfortunately addressed the wrong question. It is unable to provide the answers we need. Consistent with their previous findings[5] the authors found that, in a randomised controlled trial (RCT) setting, oseltamivir and zanamivir modestly reduced the duration of symptoms in previously healthy individuals with uncomplicated illness caused by non-pandemic, seasonal influenza viruses. Importantly, their findings do not address antiviral effectiveness in severe influenza, or in illness caused by pH1N1, or in patients with risk factors for severe illness. Therefore, these new findings cannot guide decisions about future antiviral stockpiling or the treatment of severe flu.[6]
Those responsible for pandemic planning and response had to rely on seasonal flu RCT data to make decisions on stockpiling and licensing. We now have abundant fresh evidence from the 2009/10 pandemic, including a recent systematic review of 78 observational studies (containing data from >29,000 patients hospitalised during the 2009-10 pandemic). After careful adjustments for confounding effects, it was shown that antiviral therapy was associated with significant reductions in mortality in adults, most notably a 50% reduction with early treatment.[7]
The clear discrepancy between the Cochrane group?s conclusions and the extensive, global experience of antivirals suggests that something is amiss. Observational studies have limitations, but so do RCTs and systematic reviews. Observational studies are vulnerable to bias, but stringent systematic reviews of RCTs can be misleading if the findings are not interpreted in an appropriate context. Rather than focussing on RCT data alone, we need to be pragmatic when considering how to treat flu now and in the future, and when planning how to mitigate future, unpredictable pandemics. We will serve patients best by looking at - and scrutinising - all available data, while understanding and accepting the limitations of different methodologies.
If we ignore the full range of evidence we will be misled in our management. By only accepting the narrowest of definitions of acceptable evidence, we would deny patients effective treatments and endanger public health. I encourage the Cochrane Collaboration to engage with those who are developing clinical trial protocols ahead of future outbreaks and urge them to help identify sources of independent funding. Such forward planning may prevent further confusion arising for doctors and patients, but we also require balanced communication of evidence. Clinical trial data must be transparent and open, but this issue should not be conflated with the need for deployment of safe and effective antiviral drugs.
[1] Surveillance of influenza and other respiratory viruses in the UK: 2010-11 report, http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1296687414154 (2010).
[2] Dunning, J., et al. Use of antivirals and antibiotics in pandemic influenza: findings from the UK MOSAIC study. Presented at ISIRV Options for the Control of Influenza, Cape Town, South Africa. 5-10 Sept 2013.
[3] PHE Weekly National Influenza Report: 10 April 2014 - week 15 report (up to week 14 data), http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317141076205 (2014).
[4] Jefferson, T. et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 4, CD008965, doi:10.1002/14651858.CD008965.pub4 (2014).
[5] Jefferson, T., Jones, M., Doshi, P. & Del Mar, C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 339, b5106 (2009).
[6] Jefferson, T. & Doshi, P. Multisystem failure: the story of anti-influenza drugs. BMJ 348, g2263, doi:10.1136/bmj.g2263 (2014).
[7] Muthuri, S. G. et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data (early online publication). The Lancet Respiratory Medicine, doi:http://dx.doi.org/10.1016/S2213-2600(14)70041-4 (2014).
Competing interests: When giving talks on influenza, JD has received travel and accommodation expenses and/or registration fee waivers from the following conference/meeting organisers: European Society of Clinical Microbiology and Infectious Diseases; British HIV Association; British Thoracic Society; Public Health England; Royal Society of Medicine; International Severe Acute Respiratory and emerging Infection Consortium. JD received travel and accommodation expenses from Health Protection Agency for a pandemic secondment and from World Health Organization when serving as a technical consultant on influenza. JD has contributed to the development of local and national guidelines for the clinical management of influenza. JD is an investigator in the MOSAIC influenza study, funded by the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK.
http://www.bmj.com/content/348/bmj.g2263/rr/694966