Pandemic InfluenzaOverview

衛福部 疾病管制署中區傳染病防治醫療網

王任賢 指揮官

Outline

• What is influenza?

• What is an influenza pandemic?

• History of influenza pandemics

• Control measures

Influenza

• Respiratory infection• Transmission: contact with respiratory secretions

from an infected person who is coughing and sneezing

• Incubation period: 1 to 5 days from exposure to onset of symptoms

• Communicability: Maximum 1-2 days before to 4-5 days after onset of symptoms

• Timing: Peak usually occurs December through March in North America

Clinical Presentation of Influenza

Influenza Symptoms

• Rapid onset of:– Fever– Chills– Body aches– Sore throat– Non-productive cough– Runny nose– Headache

Adapted from the National Institute of Allergy and Infectious Diseases.

Signs & Symptoms Influenza ColdOnset Sudden GradualFever Characteristic, high (over Rare

101F); lasting 3 to 4 daysCough Nonproductive; can Hacking

become severeHeadache Prominent Rare Myalgia (aches and pains) Usual; often severe Slight Fatigue; weakness Can last up to 2 to 3 weeks Very mildExtreme exhaustion Early and prominent NeverChest discomfort Common Mild to

moderateStuffy nose Sometimes CommonSneezing Sometimes UsualSore throat Sometimes Common

Influenza vs Cold Symptoms

Cox NJ, Fukuda K. Infect Dis Clin North Am. 1998;12:28.

Classic Signs & Symptoms of Influenza• Rapid onset of symptoms

• Fever, usually over 100F• Nonproductive cough

• Headache

• Myalgia

• Chills and/or sweats

• Sore throat

• Potentially severe, persistent malaise

• Substernal soreness, photophobia & ocular problems

Adapted from Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease. 5th ed. 2000:1831.

Onset of Influenza A in Volunteer

Days After Inoculation

Temp °F

Illness

Headache, Malaise, Myalgia

Nasal Obstruction and Discharge,Throat Pain, Cough

-1-1 00 11 22 33 44 55 66 77 88 2323

100100

9999

9797

Shedding of Influenza A in Volunteer

Adapted from Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles andPractice of Infectious Disease. 4th ed. 1995:1554.

0

1

2

3

4

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0 1 2 3 4 5 6 7

Vir

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log

1010 T

CID

TC

ID5

050 p

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DayDay

Influenza is a serious illness

• Annual deaths: 36,000*• Hospitalizations: >200,000** Average annual estimates during the 1990’s

• Who is at greatest risk for serious complications?– persons 65 and older– persons with chronic diseases– infants– pregnant women– nursing home residents

Complications of influenza

• Viral and bacterial pneumonia

• Myositis/myoglobulinemia & renal failure

• Myocarditis

• CNS manifestations

Respiratory complications of influenza

• Primary viral pneumonia• Secondary bacterial pneumonia• Combined viral-bacterial pneumonia• Exacerbation of COPD• Exacerbation of asthma

Viral Pneumonia Bacterial Pneumonia 2nd to Flu

Patients more at risk – Children and adults with – Age >65 yrscardiovascular disease, chronic – Patients with chronic pulmonary,pulmonary and metabolic disease cardiac and metabolic or other and hemoglobinopathies disease

– Pregnant women– Young adults (H1N1)– Immunosuppressed patients, such

as those with cancer, HIV/AIDS ororgan transplants

Clinical history Rapid progression from classic flu Improvement after classic flu symptoms symptoms, then worsening

Sputum Gram stain Predominantly normal flora – no Pneumococcussignificant evidence of Staphylococcus pathogenic bacteria Haemophilus influenzae

Moraxella catarrhalis

Chest x-ray Bilateral findings Consolidation

WBC Leukocytosis with shift to left Leukocytosis with shift to left

Adapted from Treanor JJ. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. 2000:1834-1835; Piedra PA. Semin Respir Infect. 1995;10:218.

DDx of Viral vs Bacterial Pneumonia

Patients with Indicated Bacterial Etiology (%)

0 10 20 30 40 50 60 70 80 90 100

Other Gram-NegativeOrganisms

Haemophilusinfluenzae

Mixed, IncludingStaphylococcus

Staphylococcus

Pneumococcus

Preceding Year (no influenza) During Influenza Outbreak(1968-69)

Bac

teria

l Etio

logy

The marked changes that may occur in the etiology of bacterial pneumonia during an influenza outbreak are shown in the graph above. Note that the percentage of patients with staphylococcal pneumonia more than doubles during an influenza outbreak (and is more than 2.5 times as high if staphylococci found with other organisms are included), while the proportion attributable to pneumococcal infection decreases.

Hospital Practice December 1976

Influenza Types

• Type A– Epidemics and pandemics– Animals and humans– All ages

• Type B– Milder epidemics– Humans only– Primarily affects children

Influenza Virus Composition

Type of nuclear material

Virus type

Geographic origin

Strain number

Year of Isolation

Virus subtype

A/Beijing/32/92 (H3N2)

HemagglutininNeuraminidase

Structure of hemagglutinin (H) and neuraminidase (N) periodically change:

• Drift: Minor change, same subtype– In 1997, A/Wuhan/359/95 (H3N2) virus was dominant– A/Sydney/5/97 (H3N2) appeared in late 1997 and became the

dominant virus in 1998

• Shift: Major change, new subtype– H2N2 circulated in 1957-67– H3N2 appeared in 1968 and replaced H2N2– Pandemic potential

Influenza Antigenic Changes

Timeline of Emergence of Timeline of Emergence of Influenza A Viruses in HumansInfluenza A Viruses in Humans

1918 1957 1968 1977 19971998/9

2003

H1

H1

H3H2

H7H5H5

H9

SpanishInfluenza

AsianInfluenza

RussianInfluenza

AvianInfluenza

Hong KongInfluenza

Pandemic influenza: definition

• Global outbreak with:

– Novel virus, all or most susceptible– Transmissible from person to person– Wide geographic spread

Impact of Past Influenza Pandemics/Antigenic Shifts

Pandemic, or Antigenic Shift

Excess Mortality Populations Affected

1918-19(A/H1N1)

500,000 Persons <65 years

1957-58(A/H2N2)

70,000 Infants, elderly

1968-69(A/H3N2)

36,000 Infants, elderly

1977-78(A/H1N1)

8,300 Young (persons <20)

Pandemic influenza: 2nd waves

• 1957: second wave began 3 months after peak of the first wave

• 1968: second wave began 12 months after peak of the first wave

Next pandemic: impact

Attack rate ranging from 15% to 35%:

• Deaths: 89,000 - 207,000

• Hospitalizations: 314,000 - 733,000

Source: Meltzer et al. EID 1999;5:659-71

Estimated hospitalizations due to influenza pandemic

0

200

400

600

800

1000

1200

1400

15% 20% 25% 30% 35%

National, 1 year gross attack rate

Ho

spit

aliz

atio

ns

('00

0)

95th percentile

5th percentile

Source: Meltzer et al. EID 1999;5:659-71

Mean

Estimated deaths due to influenza pandemic

0

50

100

150

200

250

300

350

400

15% 20% 25% 30% 35%

National, 1 year gross attack rate

Dea

ths

('00

0)

95th percentile

5th percentile

Source: Meltzer et al. EID 1999;5:659-71

Mean

The 1918 Influenza Pandemic

America’s Forgotten Pandemicby Alfred Crosby

“The social and medical importance of the 1918-1919 influenza pandemic cannot be overemphasized. It is generally believed that about half of the 2 billion people living on earth in 1918 became infected. At least 20 million people died. In the Unites states, 20 million flu cases were counted and about half a million people died. It is impossible to imagine the social misery and dislocation implicit in these dry statistics.”

America’s deaths from influenza were greater than the number of U.S. servicemen

killed in any war

0

100

200

300

400

500

600

700

800

900

Civil WWI 1918-19 WWII Korean Vietnam

War Influenza War War

Thousands

Spanish Influenza

• Slowed to a trickle the delivery of American

troops on the Western front.

• 43,000 deaths in US armed forces.

• Slow down and eventual failure of the last German offensive (spring and summer 1918) attributed to influenza.

Infectious Disease Mortality, United States--20th Century

Armstrong, et al. JAMA 1999;281:61-66.

Worldwide Spread in 6 MonthsWorldwide Spread in 6 Months

69,800 deaths (U.S.)69,800 deaths (U.S.)

Spread of H2N2 Influenza in 1957“Asian Flu”

Spread of H2N2 Influenza in 1957“Asian Flu”

Feb-Mar 1957Apr-May 1957Jun-Jul-Aug 1957

February 1957 – Outbreak in Guizhou Province, China

April-May 1957– Worldwide alert– Vaccine production begins

October 1957– Peak epidemic, follows school openings

December 1957– 34 million vaccine doses delivered – Much vaccine unused

January-February 1958 – Second wave (mostly elderly)

“Asian Flu” Timeline

Close calls: avian influenza transmitted to humans

• 1997: H5N1 in Hong Kong 18 hospitalizations and 6 deaths

• 1999: H9N2 in Hong Kong 2 hospitalizations• 2003:

» H5N1 in China 2 hospitalizations, 1 death

» H7N7 in the Netherlands 80 cases, 1 death (eye infections, some resp. symptoms)

Avian Influenza Poultry Outbreaks, Asia, 2003-04

Avian Influenza Poultry Outbreaks, Asia, 2003-04

• Historically unprecedented scale of outbreak in poultry

• Human cases reported from Vietnam and Thailand (as of 1/21/05: 52 cases; 39 deaths)

• No sustained person-to-person transmission identified

• Duration of the outbreak creates potential for genetic change that could result in person-to-person transmission

“The pandemic clock is ticking, we just don’t know what time it is”

E. Marcuse

Influenza Control: vaccine

– Cornerstone of prevention

– Annual production cycle ensures availability by late summer/early summer

surveillance

select strains

prepare reassortants

standardize antigen

assign potency

review/license

formulate/test/package

vaccinate

WHO/CDC)

WHO/CDC/FDA

CDC/FDA

FDA

FDA

FDA

manufacturers

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

clinic

Vaccine Development

Pandemic Vaccine

• Annual vaccine is trivalent (3 strains), pandemic vaccine will be monovalent.

• Production using current technologies would likely take 4-5 months may not be available before 1st pandemic wave

• There will be vaccine shortages initially

• 2 doses may be necessary to ensure immunity

Influenza control: antiviral medications

• Uses– Prophylaxis– Treatment

• Issues– Limited supply– Need for prioritization (among risk groups and

prophylaxis versus treatment)– Unlikely to markedly affect course of

pandemic

Influenza control: infection control

• influenza isolation precautions*– Private room or with other influenza patient– Negative air pressure room, or placed with

other suspected influenza cases in area of hospital with independent air supply

– Masks for HCW entering room– Standard droplet precautions (hand washing,

gloves, gown and eye protection)

* 1994 Guidelines for Prevention of Nosocomial Pneumonia

Infection control, cont’d

• Feasibility of these measures in a pandemic setting is questionable, priorities should include:– Droplet transmission precautions (use of

masks and hand hygiene) – Cohorting of influenza-infected patients

Influenza control: other control measures

• Education to encourage prompt self-diagnosis

• Public health information (risks, risk avoidance, advice on universal hygiene behavior)

• Hand hygiene• Face masks for symptomatic persons• School closures (?)• Deferring travel to involved areas

Influenza control: quarantine• Challenges

– short incubation period for influenza– a large proportion of infections are

asymptomatic– clinical illness from influenza infection is non

specific

• Not used during annual epidemics

• Could potentially slow onset of a pandemic before sustained person-to-person transmission has been established

Medical care during an influenza pandemic

• Surge capacity of the hospital system is limited.

• Challenges:– Magnitude and duration– Staff shortages– Limited ability to call in external resources

Despite . . . – Expanded global and national surveillance – Better healthcare, medicines, diagnostics– Greater vaccine manufacturing capacity

New risks:– Increased global travel and commerce– Greater population density– More elderly and immunosuppressed– More daycare and nursing homes– Bioterrorism

Pandemic Flu Today

抗病毒藥物

Oseltamivir Treatment: Effect on Hospitalizations

Hospitalizations % Reduction

Placebo Oseltamivir

Healthy adults 5/662 (0.8%) 3/982 (0.3%) 60%

High-risk + elderly

13/401 (3.2%) 6/368 (1.6%) 50%

Total 18/1063 (1.7%)

9/1350 (0.7%) 59% (P=0.019)

Kaiser et al. Arch Intern Med 163:1667, 2003

Oseltamivir and Complications: Retrospective Cohort Study, USA

Outcome Exposed Unexposed Adj. Hazard Ratio (95% CI)

Age 1-12

Pneumonia

Hosp.

(n=586)

4 (0.7%)

1 (0.2%)

(n=17,886)

453 (2.5%)

120 (0.7%)

0.34 (0.13, 0.90)

0.29 (0.04, 2.07)

Age 13-59

Pneumonia

Hosp.

(n=10,649)

138 (1.3%)

99 (0.9%)

(n=41,007)

885 (2.1%)

510 (1.2%)

0.81 (0.68, 0.97)

0.75 (0.60, 0.93)

Age 60+

Pneumonia

Hosp.

(n=463)

8 (1.7%)

10 (2.2%)

(n=3,298)

290 (8.8%)

163 (4.9%)

0.41 (0.20, 0.82)

0.55 (0.29, 1.05)

Nordstrom et al. 44th ICAAC, abst no. V-1260, 2004

INHALED ZANAMIVIR TREATMENT: Effect on Complications and Antibiotic Use

Respiratory events leading to antibiotics

Any event

Upper respiratory

Lower respiratory

Acute bronchitis

Pneumonia

Hospitalizations

Placebo(n=765)

18%

8%

9%

7%

2%

0.4%

Zanamivir (n=807)

13%

7%

5%

5%

1%

0.4%

RiskReduction

28%*

10%

40%*

Kaiser et al. Arch Intern Med 160: 3234, 2000 *p<0.05

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