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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”
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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!
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