Why is avian influenza so dangerous?

Thomas Fekete, MDProfessor of MedicineTemple University School of MedicineSeptember 28, 2006

Nobel laureate Peter Medawar What is a virus? “A piece of bad news wrapped in

protein”

Where did the name, “influenza,” come from? 1743, borrowed during an outbreak of the

disease in Europe, from It. influenza "influenza, epidemic," originally "visitation, influence (of the stars)," from M.L. influentia (see influence). Used in It. for diseases since at least 1504 (cf. influenza di febbre scarlattina "scarlet fever") on notion of astral or occult influence. The 1743 outbreak began in Italy. Often applied since mid-19c. to severe colds.

http://www.etymonline.com/index.php?search=influenza&searchmode=none

Influenza virus: The perennial problem

Influenza virus Most common cause of viral death in US Recognized epidemiologically for over a

century Severity and incidence vary from year to

year

ABC’s of influenza Types A and B can be epidemic

Both cause similar symptoms• Cough and other respiratory symptoms• Fever• Systemic: headache, muscle aches, fatigue•Little gastro-intestinal illness

Type A – severe epidemics Type C causes milder disease, no

epidemics

Typical influenza season One or more strains circulate Flu usually does not kill directly

Most deaths in elderly and those with underlying diseases e.g.,• Lung, heart, chronic diseases

“P & I” (pneumonia and influenza) mortality

P & I – ~ 10% of all deaths during winter peak

Annual fluctuations Total mortality from respiratory

infection always highest in winter Typically 36,000 deaths, 114,000

hospitalizations/year

2003-2004 epidemic

Severe epidemics Substantial variations year to year Pandemics have world-wide impact Three major influenza A pandemics

in 20th century 1918-1919 (H1N1) 1957-1958 (H2N2) 1968-1969 (H3N2)

Why pandemics? Delicate tension between humans

and virus Virus circulates best when not

quickly attacked by immune system Slight viral variations may be

enough to cause big problems Major shifts occur a few times per

century

Is the clue in the structure? What does the virus look like?

More detail (cartoon)

Genetics of influenza The influenza RNA has 8 segments

Segments have 1 or 2 genes Total of only 10 genes Genes evolve over time via mutation These segments can recombine in a

host cell with more than 1 virus – result: a completely new virus

Mix of variants Naming of influenza viruses

Broad variants of hemagglutinin (H) and neuraminidase (N)

Viruses have both Numbered, e.g., H1N1

• Many specific viruses within each type • Usually named for location of first isolation

e.g., H5N1 Hong Kong

Drift and shift Mutations in the genes for H and N

“Drift” (slight structure changes) Prior antibodies may recognize drifted

virus New class of H and/or N is “Shift”

No cross immunity Pandemics usually arise from shift

The other genes… In addition to hemagglutinin and

neuraminidase 3 proteins instruct on RNA replication Others are structural Some are specific to certain viruses

(e.g. M protein is only in influenza A)

Other than being new… What factors make influenza

dangerous New information about 1918 pandemic 1997 influenza A (H5N1) outbreak in

Hong Kong Current H5N1 epidemic in Asia

What about the birds?

Birds get influenza, but… The impact is different Influenza can be a diarrheal

disease Some birds die, but some birds

have asymptomatic spreading of the virus via stool

Waterfowl may have minimal symptoms and fly (and poop) far

Humans and birds Humans can get bird flu, but not

often Strains of variable severity for birds

and different species of birds affected differently

Other animals (including pigs) can be involved in transmission and combination

Not all epidemics are disastersSwine fluH1N1

1976 Limited (over)

Hong Kong H5N1

1997 Limited (over)

West Nile 1999 Continuing but minor

SARS 2003 Limited (over)

How can H5N1 infect humans? Influenza strains, in general, can

cross species This can be determined by blood tests

(e.g. antibody to bird influenza) Bird farmers can have exotic antibodies

(including non-human strains other than and including H5N1 viruses)

Usually no disease associated with these infections

This H5N1 can cause bad human disease Severe disease

Direct contact with infected birds Rapid onset of influenza pneumonia

(not secondary bacterial infection) Rapid progression to multi-organ failure Ability to infect and kill children and

young adults Reminiscent of 1918 flu

This strain seems to have person-to-person trouble Precedented

1976 swine flu Hong Kong outbreak in 1997

• 6 deaths in 18 people infected• Very slight molecular change led to highly

increased mammal pathogenicity• All domestic and commercial birds in Hong

Kong were killed to stop the epidemic

Science 7 September 2001: Vol. 293. no. 5536, pp. 1840 - 1842

Virulent variants? Crux of the issue If a bird flu becomes capable of

infecting people, it could be bad – very bad

Human to human H5N1 Several probable cases Close contact with infected people –

not with birds Incubation period compatible with

human contact (only a few days)

Preventive strategies if H5N1 spreads Don’t get infected! This might require travel

restrictions, screening, quarantine Hard to do

Seems to have been the key success for SARS, Ebola, etc.

Anti-virals Only 2 classes currently exist

“Older” drugs such as amantidine• Mechanism: prevents uncoating of virus

after it enters cell• Lost effectiveness against conventional flu• Was never “active” against bird flu

(perhaps from overuse in birds?) Newer neuraminidase inhibitors

• Drugs such as oseltamivir (Tamiflu®) and zanamivir (Relenza®)

In theory… NI should work

Can be shown to work in test tubes But human clinical experience limited Several of the bird flu deaths have been

in patients receiving oseltamivir• Was the dose too low?• Was it given too late?• Could it have been a preventive drug?

Prevention problems Assuming we would know when a flu

outbreak was about to “hit” When to start preventive therapy When to stop preventive therapy What dose to use? How to assure an adequate supply? What to do if virus becomes resistant?

The efficacy of oseltamivir is unlikely to be optimal when treatment is instituted late in the course of illness, as has been the

case in most patients with influenza A (H5N1) virus infection

reported to date. However, antiviral treatment could still be expected to be beneficial when there is evidence of ongoing viral replication. Such benefit is suggested by the rapid decline in the viral load to undetectable levels in all four survivors in the current series. In contrast, virus was still detectable at the end of treatment in three patients who died of the infection after receiving the full course of treatment, two of whom had

oseltamivir-resistant virus isolated from throat specimens. Our observations suggest that at least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication.

de Jong NEJM 2005; 353:2667

4/8 Vietnamese patients dieddespite oseltamivir treatment

Vaccine Most hopeful area

Flu vaccines are very specific If strain changes, new vaccine might be

needed Current vaccine has limited potency

• This can be improved• Hard to make enough doses for a pandemic• Expensive to do quickly, distribute

efficiently, etc.

It could go 2 ways… Sporadic cases human H5N1 disease

Fade away like SARS Stay at a low level like West Nile Excellent protective vaccine

Major pandemic Test all of our coping skills Strain our medical systems

Summary Influenza is already a killer In general, the risk is greatest in

older, sicker people Prevention is best strategy

Vaccine is safe, but gives incomplete protection

Anti-virals can be useful

Summary II Avian flu A:H5N1 can infect humans

Limited person-to-person cases so far Mortality high – even with treatment Vaccine is under development This problem may not be influenced by

the stars, but rather by the birds in the sky – Stay tuned!