Lessons for Europe from the evidence to date

Evolution of the H1N1 pandemic

European Centre for Disease Prevention and Control
Based on various talks given by ECDC staff Version 31 July 2009

About this presentation

This is an open-access ECDC Educational PowerPoint presentation, arranged in modules for use by professionals explaining about the pandemic (H1N1) 2009 to other professionals and policy makers. The slides should always be viewed with their accompanying notes, and cutting and pasting is not recommended. A number of the slides will change with time. The slides are updated at intervals, and the user should periodically check for updates available on the ECDC website: http://ecdc.europa.eu/ Comments on the slides and the notes are very much welcomed to be sent to influenza@ecdc.europa.eu. Please state 'Pandemic PowerPoints' in the subject line.
ECDC thanks the National Institute of Infectious Diseases, Japan, for the original work on Slide 3, and the Centers for Disease Control and Prevention, USA, for the original idea in Slides 4 and 36.

Pandemics of influenza
Recorded human pandemic influenza (early sub-types inferred) H2N2

H2N2 H1N1 H1N1 H3N2

1925 1955 1965 1975 1985 1995 2005
Pandemic

H3N8
1895 1905 1915

H1N1
2010 2015

1889 Russian influenza H2N2

1900 Old Hong Kong influenza H3N8

1918 Spanish influenza H1N1

1957 Asian influenza H2N2

1968 Hong Kong influenza H3N2

2009 Pandemic influenza H1N1

Recorded new avian influenzas

H7 1980
1955
Reproduced and adapted (2009) with permission of Dr Masato Tashiro, Director, Center for Influenza Virus Research, National Institute of Infectious Diseases (NIID), Japan.

H9* 1999 H5 1997 2003

1996 2002

1965

1975

1985

1995

2005

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Genetic origins of the pandemic (H1N1) 2009 virus: viral reassortment

N. American H1N1 (swine/avian/human) Eurasian swine H1N1
PB2 PB1 PA HA NP NA MP NS PB2 PB1 PA HA NP NA MP NS

PB2 PB1 PA HA NP NA MP NS
Classical swine, N. American lineage Avian, N. American lineage Human seasonal H3N2 Eurasian swine lineage

Pandemic (H1N1) 2009, combining swine, avian and human viral components

The situation could be a lot worse for Europe! (Situation circa summer 2009)
 A pandemic strain emerging in the Americas.  Immediate virus sharing so rapid diagnostic and vaccines.
A pandemic emerging in SE Asia Delayed virus sharing

Based on a more  Pandemic (H1N1) currently not that pathogenic strain, e.g. pathogenic. A(H5N1)  Some seeming residual immunity in a major No residual large risk group (older people). immunity Heightened  No known pathogenicity markers. pathogenicity Inbuilt antiviral resistance  Initially susceptible to oseltamivir.

 Good data and information coming out of transmission reached Europe North America. Arriving in the late  Arriving in Europe in the summer. autumn or winter  Mild presentation in most.
Severe presentation immediately Contrast with what might have happened and might still happen!

Minimal data until

But no room for complacency (Situation and information: late May 2009)
 Pandemics take some time to get going (1918 and 1968).  Some pandemic viruses have turned nasty (1918 and 1968).  When the pandemic wave affects Europe the health services will be challenged  There will be severely ill people and deaths in risk groups (young children, pregnant women and especially people with underlying illnesses).  As the virus spreads south, will it exchange genes with seasonal viruses that are resistant: A(H1N1)-H247Y, more pathogenic A(H3N2), or even highly pathogenic A(H5N1)?  An inappropriate and excessive response to the pandemic could be worse than the pandemic itself.

Candidate objectives of pandemic responses

 Protect citizens and visitors against the health and wider consequences of the pandemic as far as this is possible.  Through surveillance and rapid studies undertake early assessment to determine the special features of this pandemic that will inform the needed countermeasures.  Identify and protect those most vulnerable to the pandemic.  Deploy the known effective countermeasures and adapt and employ other countermeasures so that they have a net positive effect.  Apply countermeasures as effectively and equitably as possible.  Organise and adapt health and social care systems to provide treatment and support for those likely to suffer from influenza and its complications whilst sustaining other essential care services.  Support the continuity of other essential services and protect critical infrastructure.  Support the continuation of everyday activities as far as practical.  Instill and maintain trust and confidence by ensuring that the professionals, the public and the media are engaged and well informed.  Promote a return to normality and the restoration of any disrupted services at the earliest opportunity.
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Idealised national curve for planning, Europe 2009: Reality is never so smooth and simple
Proportion of total cases, consultations, hospitalisations or de aths

25%

Initiation

Acceleration

Peak

Declining

20%

15%

10%

5%

0% 1 2 3 4 5 6 Week 7 8 9 10 11 12

Single-wave profile showing proportion of new clinical cases, consultations, hospitalisations or deaths by week. Based on London, second wave 1918.
Source: Department of Health, UK

Animated slide: Please wait

One possible European scenario summer 2009

Proportion of total cases, consultations, hospitalisations or deaths 25%

Initiation

Acceleration

Peak

Declining

20%

15%

10%

5%

0% Apr May Jun Jul Aug Month Sep Oct Nov Dec Jan Feb Mar Apr

In reality, the initiation phase can be prolonged, especially in the summer months. What cannot be determined is when acceleration takes place.
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How pandemics differ and why they can be difficult

10

For any future pandemic virus can and cannot be assumed?

What probably can be assumed: Known knowns
 Modes of transmission (droplet, direct and indirect contact)  Broad incubation period and serial interval  At what stage a person is infectious  Broad clinical presentation and case definition (what influenza looks like)  The general effectiveness of personal hygiene measures (frequent hand washing, using tissues properly, staying at home when you get ill)  That in temperate zones transmission will be lower in the spring and summer than in the autumn and winter

what

What cannot be assumed:

Known unknowns  Antigenic type and phenotype  Susceptibility/resistance to antivirals  Age-groups and clinical groups most affected  Age-groups with most transmission  Clinical attack rates  Pathogenicity (case-fatality rates)  Severity of the pandemic  Precise parameters needed for modelling and forecasting (serial interval, Ro)  Precise clinical case definition  The duration, shape, number and tempo of the waves of infection  Will new virus dominate over seasonal type A influenza?  Complicating conditions (super-infections)  The effectiveness of interventions and counter-measures including pharmaceuticals  The safety of pharmaceutical interventions
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Some of the 'known unknowns' in the 20th century pandemics

 Three pandemics (1918, 1957, 1968).  Each quite different in shape and waves.  Some differences in effective reproductive number.  Different groups affected.  Different levels of severity including case fatality ratio.  Imply different approaches to mitigation.

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Age-specific clinical attack rate in previous pandemics

60%
1957 Kansas City 1957 S Wales 1957 SE London 1968 Kansas City 1918 New York State 1918 Manchester 1918 Leicester 1918 Warrington & Wigan

50%
% with clinical disease

40%

30%

20%

10%

0% 0 20 40
Age (midpoint of age class)

60

80

With thanks to Peter Grove, Department of Health, London, UK

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Different age-specific excess deaths in pandemics

4000 3500

Excess deaths

3000 2500 2000 1500 1000 500 0 <1 1-2 2-5 5-10 10-15 15-20 20-25 25-35 35-45 45-55 55-65 65-75 75+

Excess deaths, second wave, 1918 epidemic

Age group

16000 14000

Excess deaths

12000 10000 8000 6000 4000 2000 0 0-4 5-9 10-14 15-19 20-24 25-34 35-44 45-54 55-64 65-74 75+

Excess deaths second wave 1969 pandemic, England and Wales

Age group

Source: Department of Health, UK

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1918/1919 pandemic: A(H1N1) influenza deaths, England and Wales

18,000 16,000 Deaths in England and Wales 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 43 45 47 39 41 27 29 31 33 35 37 49 51 10 16 12 1918 Week no. and year 1919
Transmissibility: estimated Basic Reproductive Number (Ro) Ro = 2-3 (US) Mills, Robins, Lipsitch (Nature 2004) Ro = 1.5-2 (UK) Gani et al (EID 2005) Ro = 1.5-1.8 (UK) Hall et al (Epidemiol. Infect. 2006) Ro = 1.5-3.7 (Geneva) Chowell et al (Vaccine 2006)

1918/19: Influenza deaths , England and Wales. The pandemic affected young adults, the very young and older age groups.
Courtesy of the Health Protection Agency, UK

14

18

15

Estimated additional deaths in Europe if a 1918/19 pandemic occurred now a published worst case scenario
Austria Belgium Bulgaria Czech Rep Cyprus Denmark Estonia Finland France 13,000 14,900 47,100 34,100 1,900 7,300 6,100 8,100 89,600 Latvia Lithuania Germany Greece Hungary Ireland Italy Luxembourg Malta Iceland 13,800 18,800 116,400 27,400 37,700 6,700 95,200 500 1,100 420 Netherlands Poland Portugal Romania Slovenia Slovakia Spain Sweden UK Norway 23,100 155,200 25,100 149,900 5,000 20,600 87,100 13,300 93,000 5,800

EU total: 1.1 million

Murray CJL, Lopez AD, Chin B, Feehan D, Hill KH. Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918 20 pandemic: a quantitative analysis. Lancet. 2006;368: 2211-2218.

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1957/1958 pandemic: A(H2N2) especially transmitted among children

1,000 Recorded deaths in England and Wales from influenza

800

600

400

200

1957/58: Influenza deaths , England and Wales

Courtesy of the Health Protection Agency, UK

6 13 20 27 3 10 17 24 31 7 14 21 28 5 12 19 26 2 9 16 23 30 7 14 21 28 4 11 18 25 1 8 15 22 July August September October November December January February Week number and month during the winter of 1957/58
Transmissibility: estimated Basic Reproductive Number (Ro) Ro = 1.8 (UK) Vynnycky, Edmunds (Epidemiol. Infect.2007) Ro = 1.65 (UK) Gani et al (EID 2005) Ro = 1.5 (UK) Hall et al (Epidemiol. Infect. 2006) Ro = 1.68 Longini et al (Am J Epidem 2004)

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1968/1969 pandemic: A(H3N2) transmitted and affected all age groups

1,400 1,200 GP 'ILI' consultations per week 1,000 800 600 400 200 0

Seasonal influenza

Initial appearance

12

20

36

44

50

16

24

32

40

28

48

42

48

12

20

28

1967

1968

1969 Week no. and year

1970

1968/69: GP consultations, England and Wales

Transmissibility: estimated Basic Reproductive Number (Ro) Ro = 1.5-2.2 (World) Cooper et al (PLoS Med.2006) Ro = 2.2 (UK) Gani et al (EID 2005) Ro = 1.3-1.6 (UK) Hall et al (Epidemiol. Infect. 2006)

Courtesy of the Health Protection Agency, UK

36

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Differing attack rates determined by serology: serological attack rate observed in the UK
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79
1957

1969 (first wave)

1970 (second wave)

Courtesy of the Health Protection Agency, UK

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Idealised curves for local planning

Proportion of total cases, consultations, hospitalisations or de aths

25%

20%

15%

10%

5%

0% 1 2 3 4 5 6 7 8 Week 9 10 11 12 13 14 15

In reality, larger countries can experience a series of shorter but steeper local epidemics.
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Numbers affected in seasonal influenza epidemics and pandemics

45% 40% clinical attack rate (%) 35% 30% 25% 20% 15% 10% 5% 0%
Seasonal influenza 1918 New York State 1918 Leicester 1918 Warrington and Wigan 1957 SE London 1968 Kansas City

(Overall clinical attack rate in the first wave of previous pandemics)

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Seasonal influenza compared to pandemic proportions of types of cases

Deaths Requiring hospitalisation

Deaths

Requiring hospitalisation

Clinical symptoms

Clinical symptoms Asymptomatic

Asymptomatic Pandemic

Seasonal influenza

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Initial experience in North America 2009

23

Emerging themes in North America, late July 2009 (1)

 Early epidemic: increased influenza-like illness reports due to increased consultations; many cases attributable to seasonal influenza until mid-May.  Infection rate for probable and confirmed cases highest in 5 24 year age group.  Hospitalisation rate highest in 0 4 year age group, followed by 5 24 year age group.
Pregnant women, some of whom have delivered prematurely, have received particular attention seem to at somewhat greater risk from H1N1v than from seasonal influenza as already established.

 Most deaths in 25 64 year age group in people with chronic underlying disease.  Adults, especially 60 years and old, may have some degree of preexisting cross-reactive antibody to the novel H1N1 flu virus.  Transmission persisting in several regions of the US, but not all areas are affected.

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Emerging themes in North America, early June 2009 (2)

 Containment with impossible with multiple introductions and R0 1.4 to 1.6.  Initial focus on counting laboratory-confirmed cases has changed to seasonal surveillance methods with:
outpatient influenza-like illness, virological surveillance (including susceptibility), pneumonia and influenza mortality, pediatric mortality and geographic spread.  Stopped issuing reports of numbers of infected persons as these were meaningless.

 Serological experiments and epidemiology suggest 2008 2009 seasonal A(H1N1) vaccine does not provide protection.  Preparing for the autumn and winter when virus is expected to return:
communications: a pandemic may be 'mild' yet cause deaths; determining if and when to begin using vaccine; abandoned previous plans to use proactive school closures as this was unworkable; looking at the southern hemisphere temperate countries.

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Initial experience in Europe: Planning assumptions

26

Revised European planning assumptions for the pandemic first wave, pandemic (H1N1) 2009
Clinical attack rate Peak clinical attack rate Complication rate Hospitalisation rate Case fatality rate Peak absence rate 30% 6.5% (local planning assumptions 4.5% to 8%) per week 15% of clinical cases 2% of clinical cases 0.1% to 0.2% (cannot exclude up to 0.35%) of clinical cases 12% of workforce

These assumptions represent a reasonable worst case applying to one European country (the United Kingdom) with data available as of July 2009. They should not be used for predictions.

Courtesy of Department of Health, UK, http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_102892

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Risk groups

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Risk groups for the A(H1N1) pandemic 2009

The following groups are considered more at risk of experiencing severe disease than the general population should they become infected with the pandemic A(H1N1) virus 2009:  People with chronic conditions in the following categories:
chronic respiratory diseases; chronic cardiovascular diseases (though not isolated mild hypertension); chronic metabolic disorders (notably diabetes); chronic renal and hepatic diseases; persons with deficient immunity (congenital or acquired); chronic neurological or neuromuscular conditions; and any other condition that impairs a person s immunity or prejudices their respiratory (breathing) function, including severe or morbid obesity.

Note: These categories will be subject to amendment and development as more data become available. These are very similar underlying conditions that serve as risk factors for seasonal influenza. What is especially different from seasonal influenza is that the older age groups (over the age of 60 years) without underlying conditions are relatively unaffected by the pandemic strain.

 Pregnant women.  Young children (especially those under two years).

Sources: ECDC Pandemic 2009 Risk Assessment. Available from: http://www.ecdc.europa.eu/en/Health_topics/novel_influenza_virus/2009_Outbreak Finelli L. CDC Influenza Surveillance. Available from: http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jun09/15-2-inf.pdf Nicoll A et al. Eurosurveillance, Volume 13, Issue 43, 23 October 2008. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19018 Jamieson D et al. Lancet 2009; July 29, 2009 DOI:10.1016/S0140-6736(09)61304-0 CDC 2009 ACIP Meeting, 31 July 2009. Novel influenza A(H1N1) epidemiology update. Available from: http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jul09-flu/02Flu-Fiore.pdf CDC 2009 ACIP Meeting, 31 July 2009. Vaccine workgroup considerations. Available from: http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-jul09-flu/11-FluFiore.pdf

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Measuring the severity of a pandemic

30

There is an expectation that pandemics should be graded by severity

But there are difficulties:  severity varies from country to country;  it can change over time;  some relevant information is not available initially;  key health information includes medical and scientific information: epidemiological, clinical and virological characteristics.  There are also social and societal aspects: vulnerability of populations; capacity for response; available health care; communication; and the level of advance planning.

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What is meant by 'mild' and 'severe'? Not a simple scale

 Death ratio. Expectation of an infected person dying (the Case Fatality Ratio).  Number of people falling ill with respiratory illnesses at one time 'winter pressures'. Pressure on the health services' ability to deal with these very related to preparedness and robustness.  Critical service functioning. Peak prevalence of people off ill or caring for others.  Certain groups dying unexpectedly, e.g. children, pregnant women, young healthy adults.  Public and media perception.  Conclusions. Not easy to come up with a single measure.  May be better to state what interventions/countermeasures are useful and justifiable (and what are not).

http://www.who.int/csr/disease/swineflu/assess/disease_swineflu_assess_20090511/en/index.html and http://www.who.int/wer/2009/wer8422.pdf

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Arguments for and against just undertaking mitigation and not attempting delaying or containment
33

Policy dilemma mitigating vs. attempting delaying (containing) pandemics?

Arguments for just mitigating and not attempting delaying or containment:  Containment specifically not recommended by WHO in Phases 5 and 6.  Was not attempted by the United States for this virus.  Delaying or containment cannot be demonstrated to have worked would have seemed to have worked in 1918 and 1968 without doing anything.  Very labour-intensive major opportunity costs.  Will miss detecting sporadic transmissions.  Overwhelming numbers as other countries light up .  When you change tactic, major communication challenge with stopping prophylaxis.

34

Policy dilemma mitigating vs. attempting delaying (containing) pandemics?

Arguments for case-finding, contact tracing and prophylaxis:  Countries are then seen to be doing something.  Recommended in one specific circumstance by WHO (the rapid containment strategy).  There are some places it would work in Europe (isolated communities).  It is what public health people do for other infections.  Public may expect it.

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Aims of community reduction of influenza transmission mitigation

    Delay and flatten epidemic peak. Reduce peak burden on healthcare system and threat. Somewhat reduce total number of cases. Buy a little time.

No intervention Daily cases

With interventions

Days since first case

Based on an original graph developed by the US CDC, Atlanta

Animated slide: Press key

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