On 6 June 2017, the World Health Organization (WHO) published updates to its ‘Essential Medicines List’ (EML). Read more here.

Extended deadline (from 1 July to 31 July) 2017 for call to submit papers on effectiveness and cost-effectiveness of screening and prevention of infectious diseases among newly arrived migrants in Europe. Read more here.

Eurosurveillance is on the updated list of the Directory of Open Access Journals and in the SHERPA/RoMEO database. Read more here.

Follow Eurosurveillance on Twitter: @Eurosurveillanc

In this issue

Home Eurosurveillance Edition  2014: Volume 19/ Issue 27 Article 1
Back to Table of Contents
Download (pdf)

Eurosurveillance, Volume 19, Issue 27, 10 July 2014
Evidence and policy for influenza control
  1. Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
  2. National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia
  3. Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong Special Administrative Region, China

Citation style for this article: Kelly H, Cowling BJ. Evidence and policy for influenza control. Euro Surveill. 2014;19(27):pii=20850. Article DOI:
Date of submission: 04 July 2014

This edition of the journal includes two studies related to the control of influenza, one on neuraminidase inhibitor (NI) resistance [1] and the other on the effectiveness of trivalent influenza vaccine in the United Kingdom in 2012/13 [2]. Neuraminidase inhibitors (NIs) are the mainstay in influenza treatment and vaccination is the mainstay of prevention. It is thus important to monitor the effectiveness of both interventions over time. The current NI study demonstrates that mutations which may have had clinical significance for previously circulating seasonal influenza A(H1N1) viruses may not be clinically significant for influenza A(H1N1)pdm09 viruses, highlighting the importance of continued monitoring of NI resistance. Of equal importance is the continued monitoring of NI effectiveness [3].

Influenza is a common disease with the annual risk of influenza virus infection exceeding 20% in some years [4,5]. However the great majority of influenza virus infections do not present as the classical triad of fever, cough and fatigue [6-8], and a substantial proportion of infections, perhaps even more than half, are asymptomatic [4,5]. Even symptomatic illnesses are generally self-limiting. However a small proportion of persons with influenza virus infections will require admission to hospital, intensive care and a smaller proportion will die [9]. These outcomes are uncommon and are influenced by age, with increased risk at the two extremes of life, and the presence of co-morbidities [10]. For instance, unadjusted annual risk estimates of laboratory-confirmed influenza hospitalisation in hospitals from the Emerging Infections Program in the United States between 2005 and 2011 ranged from 20 to 72 per 100,000 for children up to the age of four years, from 16 to 76 per 100,000 for adults aged at least 65 years, but only from 5 to 14 per 100,000 for adults aged 20 to 64 years, although higher in the first year after influenza A(H1N1)pdm09 emerged [11]. About 10–30% of people hospitalised with influenza will require intensive care [12-14], and about 3–10% of patients hospitalised with laboratory confirmed influenza will die [13-15].

Because serious outcomes are relatively rare, randomised controlled trials (RCTs) in ambulatory settings for the treatment of influenza with NIs or the prevention of influenza by vaccination have not been designed with sufficient power to examine these outcomes. RCTs of antiviral drugs [16] and vaccines [17] and have shown efficacy against suspected and laboratory-confirmed influenza acquired and managed in the community but there are no RCTs investigating outcomes of hospitalisation or death due to laboratory-confirmed influenza.

It is generally acknowledged that when outcomes are rare, the RCT is not necessarily the study design of choice. The classic case–control study, in which cases and controls are ascertained retrospectively, has often been the preferred alternative design. A variation of the classic design has become increasingly popular for studying vaccine effectiveness (VE) against specific outcomes. In what is referred to as the case–test-negative design, patients with respiratory symptoms are ascertained prospectively, and vaccine coverage is compared between those who test positive and those who test negative for influenza, adjusting for potential confounders [18]. The second study of influenza in this issue of the Eurosurveillance uses the case–test-negative design in pooled community-based studies from the United Kingdom to estimate influenza VE against medically-attended respiratory disease confirmed as influenza. It reports point estimates of 73%, 26% and 51% against influenza A(H1N1), A(H3N2) and B, respectively [2]. These results confirm a number of other findings of low VE against influenza A(H3N2) in recent years [19-21], attributed to mismatch between the vaccine and circuiting strains [19]. They also highlight the importance of monitoring not only the antigenic match, as determined by serological assays, but also the genetic relatedness of circulating and vaccine viruses.

The case–test-negative design is also being increasingly used for studies of hospitalised patients, using PCR-confirmed influenza as an outcome. These studies suggest that inactivated influenza vaccines decrease the risk of hospital admission for laboratory-confirmed influenza by about half [22,23], although lower estimates have been reported for the protection against influenza A(H3N2) in the elderly [24] and higher estimates for protection against influenza A(H1N1)pdm09 [25]. A 50% decrease in risk is similar to effectiveness estimates from community observational studies using the same design [26,27], and efficacy estimates from meta-analyses of community-based trials [17].

For information on the effectiveness of NIs among hospitalised patients, we likewise need to rely on observational studies. A recent review critically examined published cohort studies assessing oseltamivir treatment for laboratory-confirmed influenza and found evidence suggesting protection against mortality in four studies, all of which were judged by the review to be of reasonable quality, and between which there was no statistical heterogeneity [28].

Even the best designed observational studies may be subject to residual bias, suggesting the need for RCTs. However RCTs of NIs in outpatients with increased risk of complications, and in patients hospitalised soon after onset of symptoms may no longer be feasible because oseltamivir is the accepted front-line treatment in groups of patients with suspected or confirmed influenza [29-31] and such trials may no longer be granted ethical approval. The same argument applies to influenza vaccination for people aged 65 years and over. For these reasons, better quality data are unlikely to be derived from RCTs, so that observational studies might do well to follow published quality guidelines in an effort to improve VE estimates [32].

Doubt has been cast on the efficacy of influenza vaccines against serious outcomes in the elderly because of the absence of trial data [33]. Similar discussions are occurring about the efficacy of anti-viral medication [3,16]. At the same time, it is being increasingly recognised that influenza infection in the community is common and that infections are associated with a wide clinical spectrum, but the serious consequences of infection are generally uncommon, and often rare, in healthy young people [5]. Improved policies for the control of influenza virus infection should acknowledge the wide clinical spectrum resulting from infection, so that prevention or treatment of serious outcomes will be attempted when serious outcomes are more likely. Such policies should use data from observational studies where trial data are absent.

Conflict of interest
BJC has received research funding from MedImmune Inc. and Sanofi Pasteur, and consults for Crucell NV. HK has spoken at a clinical training session sponsored by Sanofi Pasteur.


  1. Perez-Sautu U, Pozo F, Cuesta I, Monzon S, Calderon A, Gonzalez M, et al. Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors. Euro Surveill. 2014;19(27):pii=20849.
  2. Andrews N, McMenamin J, Durnall H, Ellis J, Lackenby A, Robertson C, et al. Effectiveness of trivalent seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2012/13 end of season results. Euro Surveill. 2014;19(27):pii=20851.
  3. Krumholz HM. Neuraminidase inhibitors for influenza. BMJ. 2014; 348:g2548.
  4. Monto AS, Koopman JS, Longini IM, Jr. Tecumseh study of illness. XIII. Influenza infection and disease, 1976-1981. Am J Epidemiol. 1985;121(6):811-22.
  5. Hayward AC, Fragaszy EB, Bermingham A, Wang L, Copas A, Edmunds WJ, et al. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med. 2014;2(6):445-54.
  6. Thursky K, Cordova SP, Smith D, Kelly H. Working towards a simple case definition for influenza surveillance. J Clin Virol. 2003;27(2):170-9.
  7. Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have influenza? JAMA. 2005;293(8):987-97.
  8. Lau LL, Nishiura H, Kelly H, Ip DK, Leung GM, Cowling BJ. Household transmission of 2009 pandemic influenza A (H1N1): a systematic review and meta-analysis. Epidemiology. 2012;23(4):531-42.
  9. Wu JT, Ma ES, Lee CK, Chu DK, Ho PL, Shen AL, et al. The infection attack rate and severity of 2009 pandemic H1N1 influenza in Hong Kong. Clin Infect Dis. 2010;51(10):1184-91.
  10. Uyeki TM. Preventing and controlling influenza with available interventions. N Engl J Med. 2014;370(9):789-91.
  11. Kostova D, Reed C, Finelli L, Cheng PY, Gargiullo PM, Shay DK, et al. Influenza Illness and Hospitalizations Averted by Influenza Vaccination in the United States, 2005-2011. PLoS One. 2013;8(6):e66312.
  12. Campbell CN, Mytton OT, McLean EM, Rutter PD, Pebody RG, Sachedina N, et al. Hospitalization in two waves of pandemic influenza A(H1N1) in England. Epidemiol Infect. 2011;139(10):1560-9.
  13. Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA. 2009;302(17):1896-902.
  14. Bagdure D, Curtis DJ, Dobyns E, Glode MP, Dominguez SR. Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU. PLoS One. 2010;5(12):e15173.
  15. Myles PR, Semple MG, Lim WS, Openshaw PJ, Gadd EM, Read RC, et al. Predictors of clinical outcome in a national hospitalised cohort across both waves of the influenza A/H1N1 pandemic 2009-2010 in the UK. Thorax. 2012;67(8):709-17.
  16. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014;4:CD008965.
  17. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(1):36-44.
  18. Foppa IM, Haber M, Ferdinands JM, Shay DK. The case test-negative design for studies of the effectiveness of influenza vaccine. Vaccine. 2013;31(30):3104-9.
  19. Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One. 2014;9(3):e92153.
  20. Sullivan SG, Komadina N, Grant K, Jelley L, Papadakis G, Kelly H. Influenza vaccine effectiveness during the 2012 influenza season in Victoria, Australia: influences of waning immunity and vaccine match. J Med Virol. 2014;86(6):1017-25.
  21. Valenciano M, Kissling E, I-MOVE case–control study team. Early estimates of seasonal influenza vaccine effectiveness in Europe: results from the I-MOVE multicentre case-control study, 2012/13. Euro Surveill. 2013;18(7):pii=20400.
  22. Puig-Barbera J, Arnedo-Pena A, Pardo-Serrano F, Tirado-Balaguer MD, Pérez-Vilar S, Silvestre-Silvestre E, et al. Effectiveness of seasonal 2008-2009, 2009-2010 and pandemic vaccines, to prevent influenza hospitalizations during the autumn 2009 influenza pandemic wave in Castellon, Spain. A test-negative, hospital-based, case-control study. Vaccine. 2010;28(47):7460-7. 
  23. Talbot HK, Griffin MR, Chen Q, Zhu Y, Williams JV, Edwards KM. Effectiveness of seasonal vaccine in preventing confirmed influenza-associated hospitalizations in community dwelling older adults. J Infect Dis. 2011;203(4):500-8.
  24. Kwong JC, Campitelli MA, Gubbay JB, Peci A, Winter AL, Olsha R, et al. Vaccine effectiveness against laboratory-confirmed influenza hospitalizations among elderly adults during the 2010-2011 season. Clin Infect Dis. 2013;57(6):820-7.
  25. Castilla J, Godoy P, Domínguez A, Martínez-Baz I, Astray J, Martín V, et al. Influenza vaccine effectiveness in preventing outpatient, inpatient, and severe cases of laboratory-confirmed influenza. Clin Infect Dis. 2013;57(2):167-75.
  26. Kelly HA, Sullivan SG, Grant KA, Fielding JE. Moderate influenza vaccine effectiveness with variable effectiveness by match between circulating and vaccine strains in Australian adults aged 20-64 years, 2007-2011. Influenza Other Respir Viruses. 2013;7(5):729-37.
  27. Ohmit SE, Petrie JG, Malosh RE, Cowling BJ, Thompson MG, Shay DK, et al. Influenza vaccine effectiveness in the community and the household. Clin Infect Dis. 2013;56(10):1363-9.
  28. Freemantle N, Shallcross LJ, Kyte D, Rader T, Calvert MJ. Oseltamivir: the real world data. BMJ. 2014;348:g2371.
  29. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60(1):1-24.
  30. World Health Organization (WHO). WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and Other Influenza Viruses. Geneva: WHO; 2010. Available from:
  31. Public Health England (PHE). PHE guidance on use of antiviral agents for the treatment and prophylaxis of influenza. Version 4.1. London: PHE; 2014. Available from:
  32. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4(10):e296.
  33. Doshi P. Influenza vaccines: time for a rethink. JAMA Intern Med. 2013;173(11):1014-6.  

Back to Table of Contents
Download (pdf)

The publisher’s policy on data collection and use of cookies.

Disclaimer: The opinions expressed by authors contributing to Eurosurveillance do not necessarily reflect the opinions of the European Centre for Disease Prevention and Control (ECDC) or the editorial team or the institutions with which the authors are affiliated. Neither ECDC nor any person acting on behalf of ECDC is responsible for the use that might be made of the information in this journal. The information provided on the Eurosurveillance site is designed to support, not replace, the relationship that exists between a patient/site visitor and his/her physician. Our website does not host any form of commercial advertisement. Except where otherwise stated, all manuscripts published after 1 January 2016 will be published under the Creative Commons Attribution (CC BY) licence. You are free to share and adapt the material, but you must give appropriate credit, provide a link to the licence, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.

Eurosurveillance [ISSN] - ©2007-2016. All rights reserved

This website is certified by Health On the Net Foundation. Click to verify. This site complies with the HONcode standard for trustworthy health information:
verify here.