1. The CAPiTA ILI study Monitoring of influenza-like symptoms among eldery, an observational study” Marieke Bolkenbaas, MD, PhD candidate Julius Center for Health Sciences and Primary Care, UMC Utrecht, The Netherlands

2. Overview Introduction and background Design and practical aspects Results

3. Introduction and background Influenza, influenza-like illness (ILI) and lower respiratory tract infections (LRTI) are common and represent an important health care problem worldwide Influenza: global annual attack rate 5-10% in adults, 20-30% in children; 3-5 million severe cases, 250-300k deaths 1 3.2 million people die of LRTI worldwide each year (ranking no. 4 in the WHO top 10 of death causes) 2 At highest risk for a worse outcome are children and elderly 3

4. Introduction and background Respiratory viruses and pneumococci are often found simultaneously during respiratory tract infections It is widely assumed that respiratory viruses like influenza facilitate secondary bacterial infection of the (lower) respiratory tract 4

5. Introduction and background Viral and bacterial respiratory tract infections often show a similar complex of symtoms and cannot easily be distinguished based on clinical signs Unknown is to what extent pneumococci play a role in the symptomatology of milder respiratory tract infections ≈80% of Dutch elderly receives annual flu vaccination 5 Pneumococcal vaccination is not (yet) recommended for 65+ year olds in The Netherlands 6

6. Monitoring of influenza-like symptoms Two ways of ILI monitoring in The Netherlands GP surveillance (sentinel network) Diagnosis by GP Max 2 nasopharynx/throatswabs each week for typing Internet-based monitoring Since 2003/2004, Great Influenza Study 7 Over 50,000 participants, most participating >1 season Self-reported symptoms of ILI and common cold Weekly questionnaire Anyone can registrate as a participant

7. Great Influenza Study

8. Internet surveillance vs GP surveillance ILI results from both systems correlated well GIS detected weekly ILI incidence trends 1 week before GP sentinel network Only 1 in 6 patients with ILI symptoms visits GP, in elderly 1 in 4 Elderly and very young relatively underrepresented in GIS Influenza vaccination % in elderly in GIS comparable with general population

9. Introduction and background CAPiTA trial 2008 - 2013 Double-blind randomized controlled trial 84,496 participants of 65+ year old Pneumococcal vaccine (PCV13) or placebo 56 hospitals and 2,200 GPs → Demonstrated effectivity of pneumococcal vaccination with PCV13 in preventing hospitalisation or death due to VT pneumococcal CAP (Bonten et al, NEJM, accepted)

10. The ILI study - design Observational study nested in the CAPiTA trial Aims: Explore the effect of pneumococcal vaccination on self-reported symptoms of ILI and LRTI Determine the incidence of ILI and self-reported symptoms of LRTI (srLRTI) Determine the proportions of episodes for which a GP is consulted

11. The ILI study – design Computer-based random selection of candidates Participation during autumn/winter seasons 2010/11 and 2011/12 Letter with instructions and login code to secured website, digital informed consent Single time questionnaire on: comorbidity, influenza vaccination status, smoking, contact with young children Weekly questionnaire on symptoms: type, duration, perceived severity, GP visit, reasons to visit, treatment by GP, use of OTC drugs Missing weekly questionnaires allowed Not possible to fill in older questionnaires

12. The ILI study – practical aspects Help and information: Telephone E-mail Website Paper user manual Weekly reminders with hyperlink

13. The ILI study – practical aspects

14. ILI study - definitions ILI - Criteria European Centre for Disease Control (ECDC): Sudden onset of symptoms AND At least one of the following symptoms: fever or feverishness, malaise, headache, myalgia AND At least one respiratory symptom: cough, sore throat or shortness of breath Self reported (possible) LRTI: Acute cough or acute worsening of cough ≥ 3 days AND At least one of the following symptoms: fever ≥38°C, shortness of breath, wheezing, chest pain or sputum production

15. The ILI study – Response

16. 2010-2011 N=7511 No. of questionnaires: 95.954 Median no. of questionnaires: 15 No. single questionnaires: 548 Median interval questionnaires: 8 days Median study duration: 126 days (7-188) 2011-2012 N=4240 No of questionnaires: 72.589 Median no. of questionnaires: 20 No. single questionnaires : 161 Median interval questionnaires: 8 days Median study duration: 170 days (7 – 212)

17. The ILI study – results – baseline PCV13 (N=3727)Placebo (N=3784)Total (N=7511) Male 2578 (69.2%)2697 (71.3%)5275 (70.2%) female 1149 (30.8%)1087 (28.7%)2236 (29.8%) age72.5 (66 – 94.6)72.4 (66.1 – 95.6)72.4 (66 – 95.6) 65-74 years 75-84 years 85 years and older 2770 (74.3%) 887 (23.8%) 70 (1.9%) 2860 (75.6%) 878 (23.2%) 46 (1.2%) 5630 (75.0%) 1765 (23.5%) 116 (1.5%) Asthma/COPD394 (10.6%)382 (10.1%)776 (10.3%) Diabetes395 (10.6%)397 (10.5%)792 (10.5%) Heart disease720 (19.3%)749 (19.8%)1469 (19.6%) Smoking (daily)188 (5.0%)224 (5.9%)412 (5.5%) Influenza vaccination3337 (89.5%)3416 (90.3%)6753 (89.9%)

18. The ILI study – vaccine effects

21. The ILI study – vaccine effects - conclusion There is no statistically significant effect of PCV13 vaccination on the incidence of ILI and self-reported LRTI symptoms

22. The ILI study – GP visits 4317 visits in 2 seasons

23. The ILI study – GP visits 4317 visits in 2 seasons

24. The ILI study – what next? Duration of symptoms Effects of ILI and srLRTI on daily activity level Coupling of data with pneumonia/LRTI data of GP practice and hospital pneumonia data -> comprehensive view on clinical course of lower respiratory tract infections

25. Questions?

26. Reference list 1.WHO, Factsheet no. 211 Seasonal Influenza, March 2014 www.who.intwww.who.int 2.WHO, Factsheet no. 310 The Leading 10 Causes of Death, May 2014 www.who.int 3.Voordouw AC, Sturkenboom MC, Dieleman JP, Stijnen T, Smith DJ, van der LJ, et al. Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. JAMA 2004 Nov 3;292(17):2089-95. 4.Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008 Oct 1;198(7):962-70. 5.Jansen AG, Sanders EA, Nichol AL, Van Loon AM, Hoes AW, Hak E. Decline in influenza- associated mortality among Dutch elderly following the introduction of a nationwide vaccination program. Vaccine 2008 Oct 16;26(44): 5567-74 6.Health Council of the Netherlands. Pneumococcal vaccine in elderly adults and risk groups. Health Council of the Netherlands. 18-8-2003. 18-8-2003. 7.Friesema IH, Koppeschaar CE, Donker GA, Dijkstra F, van Noort SP, Smallenburg R, et al. Internet-based monitoring of influenza-like illness in the general population: experience of five influenza seasons in The Netherlands. Vaccine 2009 Oct 23;27(45):6353-7 8.ECDC. Influenza case definitions. http://www.ecdc.europa.eu/en/activities/surveillance/EISN/surveillance/Pages/influen za_case_definitions.aspx