The orthomyxoviridae viruses.
The orthomyxoviridae our large,
enveloped viruses with a helical capsid,
such as you can see on the colored scanning
electron micrograph to the right.
They are or they have a linear,
negative-sense, segmented RNA genome,
and thus must carry an RNA-dependent
They're able to replicate within the nucleus,
even though they have their own
The important viruses in this family are
the influenza viruses, types A, B, and C.
And these, of course, will be quite
familiar to you as the cause of
pandemic and epidemic flu.
What is the structure of the
influenza virus? And in fact,
it is well known for having
and neuraminidase glycoproteins,
which you see identified
on the cartoon in the right side.
Both are present at the
surface of the virus,
and both have different medical
Both can be targets, though,
and in the case of neuraminidase,
a target for treatment.
Within the helical capsid are
and also, the RNA-dependent RNA
polymerase, the RDRP.
In addition, influenza A especially,
contains M1 and M2 proteins
important for virion assembly.
And then for M2, it's a target for
some other antiviral drugs.
How do we think about these influenza
viruses, and specifically,
how do they serve as examples for
antigenic drift and shift?
Now, to explain the concepts of drift
and shift, you first need to know
that as you sit here watching
very exciting session, you
yourself are mutating.
Well, in fact, your DNA or your RNA
are undergoing constant point mutations.
In human beings, we have a repair mechanism
which corrects or fixes those mutations.
And so, if I suddenly change
a T to an A, it'll be changed back to a T.
Influenza, both A and B, does not have
such a repair mechanism.
And so, those natural spontaneous
mutations that the influenza
genome undergoes, are not repaired.
As these mutations occur, and each one
by itself has no major effect,
but as they continue to occur
then ultimately -- and this may be a period
of hours, days, weeks, months --
ultimately, there may be sufficient mutations
within a genome or a gene,
which actually changes the
transcription of that gene
and changes the protein product.
So, it's minor changes, and when they occur,
they will change the hemagglutinin or
the neuraminidase genes,
which will change the antigenic
recognition of the influenza A,
and we have the effect of a new virus
affecting the world leading to an epidemic.
So, antigenic drift,
slow, gradual, very much like an iceberg
drifting slowly, slowly, slowly on the ocean.
In direct contrast is antigenic shift.
This is a dramatic change,
and it involves reassortment of different
genes between different influenza viruses.
And this may be from a reassortment between
a human strain and an animal strain.
For example, the avian flu, if you all
remember that outbreak,
was a reassortment between poultry
and between the human strain.
Most of the reassortment occurs, sorry to
tell you this, between humans and pigs.
Yes, we share some interactions with
our dear friends, the pig kingdom.
So, as a reassortment occurs
between those 2,
then we get in the space of a rapid
reassortment, so, you know,
days to weeks, a brand new,
significantly different or
especially influenza A, which
nobody has seen,
and it's completely separate from
prior viruses out there.
So there is no antibody
When that happens, then one has a pandemic.
Not just a limited blip of flu occurring
during the winter season,
but worldwide, many more cases,
higher severity, higher numbers, etc.
And this most recently happened in 2009
with the influenza H1N1 pandemic.
Now, the problem with these antigenic shifts
is that they can occur dramatically,
meaning there's a lot more virus out there,
and that increases the ability to be
affected with 2 strains at the same time.
And when that occurs, that further allows
mixing of genome segments to occur,
not just in humans that are, thankfully,
inefficient mixing pots,
but in other animals. Again, the pig
is an ideal mixing pot
for such interagency to occur.
So that means that hybrid viruses
can continue to occur
in the setting of a pandemic.
Basically, a whole lot influenza, which
all of us are susceptible to.
So, let's look at the diseases caused
by the influenza viruses,
and we break these down into classic
influenza in adults and in children.
Children may, as you will see, present
a little bit more dramatically,
and children are also very
effective mixing pots
because their immunity is
slightly less mature.
And that also allows for them to
have higher viral expression
and for them to be highly contagious.
So, both adults and children have a
incubation period with influenza
of just 1-3 days. It's a very short process.
The transmission, of course, very effective
through respiratory droplets,
hence the public health recommendations to
cover the cough and sneeze into
the crook of the arm.
Prodrome for both is from maybe 3-
24 hours, not days, but hours.
Children may not report the
malaise or headache
because they're too busy doing other things,
having fun, eating dirt, etc.
But when disease occurs, then both adults
and children will have fever,
but the children will have a higher fever.
Adults have the fever along with the
myalgias, so severe muscle aches.
They may have a dry, nonproductive cough.
In adults, they'll have secondary
Staphylococcus aureus, Streptococcus
Haemophilus influenzae caused pneumonia.
Children may get the pneumonia, but
they may also get otitis media,
they may get bronchiolitis, sort of
upper and lower respiratory disease.
They may have croup.
Certainly, they may have more of a gastro-
intestinal component to their influenza,
but that's not limited to children either.
So you can see some cross
symptoms between the 2,
but if you had to distinguish adult
versus childhood influenza,
it's really the height and
severity of the fever.
Overall severity, although anybody
who's in the middle of suffering
from the flu would argue with me
extensively, but overall,
it's a relatively mild, minor, self-resolving
process if one is immunocompetent.
Now, those who are immunodeficient
can have severe disease,
which can progress to respiratory
failure and death.
Those individuals would be pregnant women,
a person with known immunodeficiency,
or even patients with
The rest of us may be completely
asymptomatic, if we're lucky,
all the way up to how -- to a
very severe process,
depending on how much of an immune
reaction we actually have.
The complications, and these are
actually also contributors
to the mortality, the death rate, associated
with outbreaks of influenza.
In adults, the bacterial super
pneumonia, and also in some cases,
especially with influenza B,
there's a postinfluenza encephalitis.
In children, a myositis.
Some children who are still mistakenly
treated with aspirin
are at risk for Reye's syndrome
or fulminant hepatic failure.
But again, that's more due to
ingestion of aspirin or so.
So, overall, the severity depends upon age,
and then to a secondary extent, the
immune function of the patient.
The diagnosis of influenza
is best performed via nucleic acid
detection methods, which have both high
sensitivity and specificity.
These exist as conventional PCR, such
as RT-PCR and multiplex PCR.
That Multiplex PCR typically
will detect other respiratory
and respiratory bacterial pathogens.
Time to complete these PCR tests
usually is from one to 8 hours,
and they have, as noted, very high
sensitivity and very high specificity.
They can differentiate influenza A
and B and also can differentiate
the subtypes of Influenza
A, such as H1N1 versus H3N2.
method is a rapid nucleic acid detection,
and this typically can take from 15
to 30 minutes to complete.
So a point of care test, for example,
in an emergency department.
This can differentiate
and detect influenza A and B,
but it cannot sub differentiate
the influenza A subtypes.
Other tests exist
such as antigen detection assays.
These are rapid from 15 minutes up
assays taking one to 4 hours.
negative results are common,
so these should only be used as screening
Viral culture is possible but
is not useful because it takes a long time
and is really only used for public health
reasons and for serologic
excuse me for therapeutic testing
Serology itself is not useful
because it doesn't
distinguish very actively
active versus past infection.
Prevention. Vaccination, vaccination,
Yes. An annual vaccination for
influenza is created
based on predictive probability
in a single country looking at influenza
in the other hemisphere saying,
"All right." So in the States,
we look at information coming from
Australia to say, "Okay, they're having
these strains of influenza A and B,
meaning that when we have our flu season,
we're more likely than not going
to have the same strains."
So, based on predicted endemic strains,
the vaccine is created to provide
coverage to those.
Treatment of influenza
if started with an antiviral drug,
it must be started within 48 hours
of onset of symptoms
to have any discernible,
proven impact on the outcome.
However, these treatment track drugs
can also be used for post-exposure
The classes of antiviral drugs
are the neuraminidase inhibitors.
the influenza virus neuraminidase enzyme,
which prevents release of viral particles
from infected cells.
are active against both Influenza A and B.
include oseltamivir and oral medication
zanamivir, which is inhaled
and of course contraindicated
if the patient has chronic lung disease
such as asthma or COPD,
and then peramivir,
which is given intravenously.
The next class of influenza treatment
are the endonuclease inhibitors.
These inhibit initiation
of mRNA synthesis and are active
also against influenza A
and B. Baloxavir,
an oral drug is
and is an example of this class.
And then the Adamantanes
which target the M2 protein of influenza
A only. This protein forms
a protein channel in the viral membrane
and is essential for viral replication.
So of course preventing it from acting
will prevent viral replication.
only are active against Influenza A,
but unfortunately there are no long
due to high rates of resistance,
both in the States and elsewhere.
The two drugs
that are examples in this class
though, are amantadine and rimantidine.