What have we learned from the 2009 pandemic?

Allison McGeer, MSc, MD, FRCPC Mount Sinai Hospital University of Disclosures

 Investigator initiated research funding: – Hoffman LaRoche, GlaxoSmithKline, Sanofi- Pasteur  Advisory Boards – Novartis, GlaxoSmithKline, Sanofi-Pasteur, Pfizer, Hoffman-Laroche  Honoraria for lectures – GlaxoSmithKline, Hoffman-Laroche, Gilead Biosciences

Schematic diagram of the influenza viral life cycle.

G Neumann et al. Nature 459, 931-939 (2009) doi:10.1038/nature08157

Viral shedding Annual Influenza in Canada (Pop 33M)

 5 million (1 in 6) infected per year

 ~50,000 hospitalizations – 1% of those >65yrs; 0.5% of those <1yr

 4,000 - 8,000 deaths (10 in children)

 7% of children get otitis media

 1.5 million work-days lost Antigenic drift

Treanor J. N Engl J Med. 2004;350:218-220. Smith et al. 2004 Evolution of New Viruses

16 HAs 9 NAs Avian Human virus virus

Reassortant Swine virus virus Figure from Smith et al. 2009 Nature. In press: doi:10.1038/nature08182. History Be an influenza virus, see the world

Epidemic curve of pandemic (H1N1) 2009 hospitalized cases, ICU admissions and deaths in Canada by date of onset, as of December 19, 2009*

200

Hospitalized cases ICU admissions Deaths 150 ILI-rate/1000 Lab %+ve

100 & Lab %+ve ILI rate/1000 Laboratory-confirmed cases

50

0 4-Jul-09 3-Oct-09 6-Jun-09 5-Dec-09 5-Sep-09 7-Nov-09 1-Aug-09 8-Aug-09 2-May-09 9-May-09 11-Jul-09 18-Jul-09 25-Jul-09 10-Oct-09 17-Oct-09 24-Oct-09 31-Oct-09 11-Apr-09 18-Apr-09 25-Apr-09 13-Jun-09 20-Jun-09 27-Jun-09 12-Dec-09 19-Dec-09 26-Dec-09 12-Sep-09 19-Sep-09 26-Sep-09 14-Nov-09 21-Nov-09 28-Nov-09 15-Aug-09 22-Aug-09 29-Aug-09 16-May-09 23-May-09 30-May-09 Symptom onset date (or specimen collection date)

*Symptom onset date/specimen collection date was available for 98% of hospitalized cases and ICU admissions and 99% of deaths. What’s next? - Pandemic

 There will be another pandemic – ~3% risk per year

 Severity of next pandemic is unpredictable

 Goal is planning that is: – Efficient (but recognizes that insurance is important) – Fills the gaps we identified in 2009 pandemic – Sustainable What’s next? - 2010/11 season

 Activity around the world is mixed – A(pH1N1) – A(H3N2) – B/Victoria  So, 2010/11 season could be any strain

 Very few isolates so far, so no indication that season is starting Timing and Prevalence of Influenza Depends on Season

Percent Positive Influenza Tests, Compared With Other Respiratory Viruses, Canada, by Reporting Week, 2005-2006 % Positive Tests 30 November - April 35

20

15

10

5

0 35 37 39 41 43 45 47 49 51 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 2005 Report Week 2006 % positive influenza virus % positive respiratory syncytial virus % positive parainfluenza virus % positive adenovirus

Public Health Agency of Canada. FluWatch. August 13, 2006, to August 26 2006 (Week 33 & 34) .

18 What’s next? - 2010/11 season

 Patient messages about influenza vaccine – Made exactly the way we have always made seasonal influenza vaccines – More the 100M people around the world have been vaccinated with pH1N1 containing vaccines – Influenza continues to kill more Canadians than any other infectious disease – vaccination is the best prevention Motivation to Get the Flu Shot

 Ontarians would be more likely to get the flu shot if–

 There was a large outbreak in Ontario (73%)

 They were convinced the flu was a serious disease (73%)

 Their doctor recommended it (69%)

 It was offered in a convenient location (64%)

 They knew more about it and what it does (60%)

Ontario Ministry of Health and Long-Term Care, August 2010 21 Why should Ontarians get the flu vaccine?

 Every year, Ontario’s Universal Influenza Immunization Program saves– – 300 deaths – 1,000 hospitalizations – 30,000 visits to hospital emergency departments – 200,000 physicians’ consultation for illness

Kwong JC, et al. PLoS Med 2008;5:e211 What’s next? - 2010/11 season

 Patient messages about influenza vaccine – Made exactly the way we have always made seasonal influenza vaccines – More the 100M people around the world have been vaccinated with pH1N1 containing vaccines – Influenza continues to kill more Canadians than any other infectious disease – vaccination is the best prevention – Influenza vaccination does not make you sick Adverse Effects after Influenza Vaccine

Symptom Percent reporting symptom in 7 days post- injection Fever 6.1 Tiredness 19.4 Malaise 17.5 Myalgia 5.7 Headache 14.4 Sore arm 24.1

Nichols et al. Arch Int Med, 1996;156:1546 Adverse Effects after Influenza Vaccine

Symptom Placebo Vaccine Fever 6.1 6.2 Tiredness 19.4 18.9 Malaise 17.5 16.0 Muscle aches 5.7 6.2 Headaches 14.4 10.8 Sore arm 24.1 63.8

Nichols et al. Arch Int Med, 1996;156:1546 2010/11 Vaccination New for physicians

 More evidence on prevention of cardiac disease

 New evidence about GBS

 New evidence about influenza and vaccination in pregnancy 26 Flu Vaccine Associated with Reduced Rate of Acute MI

 UK: 16,012 pts >40 years with first acute MI vs. 62,694 matched controls1

 Influenza vaccination associated with– – 19% reduction in acute MI when given within the past year – 20% reduction in acute MI when given within the flu season

 Greater reductions in MI seen with vaccination early (ie, Sept to mid­Nov) vs. later in the season (21% vs. 12% vs. no vaccination)

 Influenza vaccination should be encouraged wherever indicated, especially in people with existing CV disease, among whom there is often suboptimum vaccine uptake2

1. Siriwardena A, et al. CMAJ 2010 Sep 20. [Epub ahead of print] 2. Warren-Gash C, et al. Lancet Infect Dis 2009;9:601-10 27

Influenza Vaccine and GBS

 Guillain-Barré Syndrome (GBS) occurs in ~2 of 100,000 people per year, usually due to food-borne infection1

 GBS occurrs in association with the flu vaccine - rarely – 1.2 cases per million doses1 2  Influenza infection itself can cause GBS

 Vaccination not associated with overall increase in the risk of GBS2,3 – Risk of GBS after ILI: 17 (9.4, 25) – Overall risk of GBS in vaccinated: 0.58 (0.18, 1.9)

1. PHAC. http://www.phac-aspc.gc.ca/alert-alerte/h1n1/pdf/Factsheet_Seniors.pdf 2. Sivadon-Tardy V, et al. Clin Infect Dis 2009;48:48-56 3. Tam CC, et al. PLoS One 2007;2:e344 Benefit of vaccinating pregnant women

Outcome Reduction associated with influenza vaccine Influenza in infants 63% (5,85)

Febrile respiratory illness 29% (7,46) in infants Febrile respiratory illness 36% (4,57) in mothers

Zaman K, NEJM 2008;359:1555 Adjusted odds ratios of prematurity and small for gestational age by maternal influenza vaccine status (OR <1 imply a protective vaccine effect of )

Small for Gestational Premature Age Odds Ratio p Odds Ratio Analysis Period p value (95% CI) value (95% CI) All seasons/periods 0.8 (0.6-1.1) 0.18 0.9 (0.6-1.3) 0.66 Putative influenza season (Oct- 0.6 (0.4-0.9) 0.01 0.8 (0.5-1.3) 0.42 May) Period of at least local 0.5 (0.3-0.9) 0.02 0.7 (0.4-1.3) 0.24 influenza activity* Period of widespread influenza 0.3 (0.1-0.7) 0.01 0.4 (0.2-1) 0.04 activity* Influenza in pregnancy and birthweight RCT, Bangladesh, 2004/5

 Difference in birth weights (vaccine vs. placebo) during intervals with no influenza – neonates of vaccinated moms babies were 0.25 gms heavier (P=.70)

 Difference in birth weights during intervals with influenza activity – neonates of vaccinated moms were 215 gms heavier (P=.004) Influenza vaccine in pregnancy Safety data

 No pregnancy associated adverse events with ANY inactivated vaccine, EVER  Vaccine is recommended in pregnancy by NACI, CDC, SOGC, ACOG1,2 – Numerous safety studies, no evidence of teratogenicity

 No evidence to suggest that thimerosal given to mothers has any impact on fetus – Since 1998, US has recommended vaccination of pregnant women - 500,000 to 2 million/yr x 11 years

Dosing of Influenza Vaccine for Children <9 Years of Age*

Dose (ml) Number Site of doses† Anterolateral Age 6-11 months 0.25 ml 2 thigh Age 12-35 months, no previous dose any 0.25 ml 2 Deltoid SEASONAL influenza vaccine Age 12-35 months, at least one prior 0.25 ml 1 Deltoid dose any SEASONAL influenza vaccine Age 3-8 years, no previous dose any 0.5 ml 2 Deltoid SEASONAL influenza vaccine Age 3-8 years, at least one prior dose 0.5 ml 1 Deltoid any SEASONAL influenza vaccine

*Adults and children over 9 years of age should receive a single 0.5 ml dose IM in deltoid †Doses should be given 4 weeks apart. NACI. Can Commun Dis Rep 2010;36(ACS­6):1-49 Key Messages About Influenza Prevention

Get the flu shot Wash hands with soap and water at least 5 times per day Keep an alcohol-based hand sanitizer handy at work, home and in your car (minimum 60% alcohol) Cover the mouth and nose with a tissue to cough or sneeze and throw the tissue out. Cough into the upper sleeve if a tissue isn’t available Stay home when sick. Avoid crowds where viruses can spread easily Keep common surfaces and items clean New in Testing and Treatment

 Many cohorts from pH1N1 that find an association between treatment, especially early treatment, with antivirals, and increase survival Cohorts pH1N1 - I Antiviral efficacy

Reference Patients NI impact Dominguez-Cherit Mexico, 58 OR survival if RX JAMA 2009;302:1883 critically ill 8.5 (1.2,63) Van Tam First 631 hosp OR for survival if Rx Thorax 2010;65:645 cases, UK NS (univ. OR 2.0) Zarychanski LCI, Manitoba <2 days to Rx, OR survival CMAJ 2009 8.2 (2.8, 24) Yates Pregnant <2 days to Rx HTAS 2010;14:109 women, UK OR ICU admit 0.16 (.08,.34) Jain 272 hosp OR survival increased with NEJM 2009; 361:1935 patients, US shorter time to therapy Cohorts pH1N1 - II Antiviral efficacy

Reference Patients NI impact Lee 47 NYC deaths Fatal cases less likely to CID 2010;50:1498 (CC) receive NI, rcvd later (p<.01) CUI 68 hosp, No effect BMCID 2010;10:145 Shenyang, China Kumar 237 SOT pts Delayed antiviral predicts Lancet ID 2010;10:521 ICU (OR 3.0, P=.02) Testing recommendations

 Test when it will make a difference to management – Kids in ED, if an influenza diagnosis means you don’t need antibiotics or admission – Adults being admitted to hospital with pneumonia/COPD exacerbation/sepsis NYD Treatment recommendations

 Use antivirals: – During influenza season – <48 hours after symptom onset, or not improving/getting worse – WITH fever, sudden onset, early cough – WITH risk factor for severe disease

 Choice of antivirals – Oseltamivir 75 mg bid x 5 days – Zanamivir 10mg (2 puffs) bid x 5 days In sum

 Influenza remains the most common infectious disease cause of death in Canada  Vaccination is our most important preventive strategy – Biggest gap is those who don’t get vaccinated – Pandemic confusion will impact vaccination rates this year – Physician recommendation is critically important

 Antivirals are an useful adjunct to Questions?