Fekete Sept2806

Why is avian influenza so dangerous?

Thomas Fekete, MD Professor of Medicine Temple University School of Medicine September 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

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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 

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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 ď Ž Typically 36,000 deaths, 114,000 hospitalizations/year ď Ž

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? ď Ž

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 

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New class of H and/or N is “Shift” 

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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…   

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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 disasters Swine flu 1976 H1N1 Hong Kong 1997 H5N1

Limited (over)

West Nile

1999

Continuing but minor

SARS

2003

Limited (over)

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 

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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?)

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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? 

4/8 Vietnamese patients died despite oseltamivir treatment 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 oseltamivirresistant 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

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 

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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 

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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! 