- Welcome, everyone to
Wednesday Nite @ the Lab.

I'm Tom Zinnen.

I work here at the UW-Madison
Biotechnology Center.

I also work for the Division
of Extension and Wisconsin 4-H,

and on behalf of those folks
and our other co-organizers,

PBS Wisconsin, the Wisconsin
Alumni Association,

and the UW-Madison
Science Alliance,

thanks again for coming to
Wednesday Nite @ the Lab.

We do this every Wednesday
night, 50 times a year.

Tonight, it's my pleasure to
introduce to you Katie Schmit.

She's a physician in the
Department of Pediatrics here.

She was born in St.
Charles, Illinois,

which is right down Illinois
38 from Dixon, Illinois.

She went to St. Charles
North High School,

and then came here to UW-Madison
to study biochemistry.

Then she went to
St. George's University

to get her medical degree
on the island of Grenada,

then she did her
clinical work in Brooklyn

and lived in Bedford-Stuyvesant.

Then she came here to
UW-Madison to do her residency.

She's currently here
doing a fellowship

in pediatric infectious disease,

and she's also doing a primary
care research fellowship

with the Department
of Family Medicine.

Tonight, she's going to
talk to us about something

that's near and
dear to all of us

who have ever had children,

respiratory viruses of
children and adults.

The focus is on influenza.

It's gonna be interesting to
see how the numbers stack up

to this competing virus that
we have going around right now.

I think influenza may win.

Please join me in
welcoming Dr. Katie Schmit

to Wednesday Nite @ the Lab.

[audience applauding]

- All right.

Thank you, Tom, for
that introduction.

Today, I'll be discussing
influenza, like Tom mentioned.

I will focus on three key
concepts that will help us

follow influenza
from the virus itself

to the infection that it causes.

So my goal is to help you
guys enhance your knowledge

about influenza you
hear so much about,

and the flu virus you
hear so much about.

I recognize that
everyone in this room

is starting from
different backgrounds.

There may be some
virologists in the audience,

but I'm trying to
keep it quite basic

with talking about key
concepts about influenza

that transfers over to
different respiratory viruses.

So before I get started, I
have no financial disclosures.

[audience chuckling]
I will not be addressing

any non-FDA medications
during this talk.

So these are the
three key concepts

that I'll be going through
today to talk about

in addressing influenza.

So even though some of these
are very specific and unique

to influenza, overarching
respiratory viruses,

a lot of this is the same
in regards to transmission

and immunity, and
within transmission,

animal to human transmission

as well as human to
human transmission.

So the first concept I'll
go over is viral properties

that are unique to influenza,

dealing with some surface
antigens called hemagglutinin

and neuraminidase, and then
going to antigenic drift

and shift, which really
helps us understand epidemics

and pandemics and
how they occur.

Second concept I'll
go to is transmission.

So this is focusing more on
the human to human transmission

that occurs with droplets
transmission mainly,

and then also discussing some
of the environmental changes

that allow influenza
to replicate.

The third concept
that I'll go through

has to do with immunity.

So not only population immunity,

but I will talk about
influenza vaccine overall.

So I know I listed a whole
bunch of things on that slide.

Some things may be
familiar to you,

some things may be
completely foreign,

so I really don't want you
guys thinking like this

at this point.

I really want us to take
this journey together

and have a better
understanding idea

of some of these concepts
that come through

when we talk about influenza.

So my goal is to put
you more in this realm.

Being able to talk to family
and friends about influenza,

being more informed,
yourself, about influenza

and some other
respiratory viruses.

Realistically, I know that
you may feel more like this

after my talk, and that's okay,
but I'm hoping that we land

more on this, where we
just really understand

the importance of hand
washing and the key things

with influenza and other
respiratory viruses

to reduce transmission overall.

So before I go into those key
concepts that I talked about,

I'm gonna start with
the burden of influenza.

So this is important,

and why I'm talking
about influenza today

has to do with the burden
of disease that we see

in the United States and
throughout the world.

So these statistics here,
I'll try not to bore you

with a ton of statistics,
but these statistics here

are just from this
influenza season.

So starting from September to
this is the most recent one

on the CDC from February 22nd.

These are the numbers
that we're dealing with.

So when we talk about
flu illnesses overall,

we're at 45 million flu
illnesses in the United States.

Okay.

So this isn't world, this is
in the United States, here.

We're talking about 500,000
influenza hospitalizations.

So to put that in perspective,

that's about the
size of Milwaukee.

A little bit less than the
size of Milwaukee, overall.

So the entire city of Milwaukee

would be hospitalized
with influenza.

In addition to that, when
we look at flu deaths

so far this season alone,

we're at 18,000 to
46,000 influenza deaths,

which is quite a lot
when we're comparing it

to some other things that
are going on at this time.

Overall, the CDC tracks all of
the leading causes of death,

and in 2017, which is
the most updated ones

that they have, it is the
eighth leading cause of death.

So influenza and
pneumonia combined

are the eighth leading
cause of death overall.

So this is really important,
and something I think

a lot of us forget about, is
how big of a burden this is.

This is also from the CDC, the
Center for Disease Control.

I'll abbreviate it as
the CDC going forward.

This has to do with
the median incidence

of symptomatic influenza
throughout the influenza years

from 2010 to 2015
influenza seasons.

So the seasons' severity
change quite a bit

from moderate, to low, to high
depending on certain types

of viruses that are
circulating that year,

but overall, with all ages,
this is the amount of people

that have symptoms
because of influenza.

So 8.3% of the total population
has influenza symptoms

throughout the influenza season.

Then, when we look at
specific age groups overall,

we notice that the children
less than five years of age

have a higher percentage,
and also adults age 50 to 64

also have a higher percentage.

Again, every season it
changes a little bit,

there's some certain
seasons that it shifts,

but really these are the ages
that are affected the most.

The deaths per year
in the United States,

it's 12,000 to 61,000.

Again, that changes depending
on the circulating viruses

and some of the other things
I'll talk about moving forward.

But worldwide, there is 290,000
to 646,000 deaths per year.

The entire world.

Okay, so that addresses
just some of the burden,

and why I think it's important
to talk about influenza,

and why we should be educated
about influenza overall.

So now I'll go into
the viral properties

I was talking about.

So these are specific
to influenza

and help with influenza
being virulent,

and how it gets transmitted
to others.

So first, I'm gonna talk
about the two surface proteins

that are important,
hemagglutinin and neuraminidase.

So this is a depiction
of the influenza virus

that really graphically helps.

So influenza virus
is an RNA virus.

This is important when we
talk about some of the changes

that the virus can
have moving forward.

So its genome, so the
genetic makeup of this virus

is RNA instead of DNA, which
our genetic makeup is made of.

So now, moving onto
some surface proteins.

So the first one I wanna
talk about is hemagglutinin,

which is, really how
you think about it

is this the virus here,
and how it sticks to cells,

and how it's glued to a cell

is the protein
called hemagglutinin.

So this is the reason
that the influenza viruses

attaches to cells.

Moving forward, it's
abbreviated as HA or H.

I'll come into influenza
naming in a little bit.

The second surface
protein that you can see

on this picture here is
something called neuraminidase,

which helps release the
virus from the cell.

So after the virus is attached,

it gets engulfed into the
cell, it makes new virus,

and then prior to it
getting out of the cell,

it needs to be
released by something.

And this is what is releasing
it, the neuraminidase.

So you can think about
the neuraminidase

as a scissor, okay?

So the hemagglutinin
glues it to the cell,

the neuraminidase cuts
it off from the cell.

Moving forward, this will
be abbreviated as NA or N.

And so, these are important
when we talk about

some of the naming
of influenza viruses.

So if you guys have heard
of influenza viruses

named H1N1, H3N2, H2N2,

those are why they're
named that way

is based on these
surface proteins.

So the H refers
to hemagglutinin,

the N refers to neuraminidase.

So now, we'll go through
the life cycle of influenza.

So once it attaches
to the epithelial cell

of either humans or animals,
what it does is that virus

goes into the cell, over
on the second portion here,

and that is facilitated,
the actual attachment

like we talked about,
is the hemagglutinin,

goes into the cell, and then
it releases its viral contents

in that third stage, in
the uncoating stage.

Once its viral contents
are in the human cell

or animal cell, it then
transfers its RNA material

into the nucleus of that cell,

and then what it does
is it replicates it.

So it makes more of itself,

making more of these
infectious viral particles

that you can see
within the cell, here.

And then, once it's ready,
it goes to the cell's surface

and then it gets released,

and that's where the
neuraminidase comes in

and it helps with the process.

So there are three different
types of influenza,

type A, type B, and type C.

So first I'll mention type C.

Type C is not something
we hear about very often,

but it is a subtype
of influenza.

It typically causes very
mild respiratory illnesses

in children.

We don't focus on it as much

because it doesn't lead
to pandemics or epidemics,

so it doesn't lead to mass
people having infections

because of it, and the
symptoms are quite mild

so we don't see deaths
associated with it.

This is the last time
I'll talk about type C,

'cause really, the
importance of the influenza

has to do with type A and B.

So now, talking about type
A, as I mentioned previously,

type A is named by the H#*N#*

or H#N# subtypes.

When we look at different
subtypes like I had mentioned,

there are certain subtypes
that infect different types

of animals and different
types of humans.

So influenza A is quite unique

because it can infect
birds, can infect pigs,

and it can infect humans.

So this becomes important when
we talk a little bit later

about some of the pandemics
that have happened in the past.

And concern for pandemics
happening in the future

really has to do
with multiple species

being able to be infected
with influenza A virus.

Humans, at this time,
have only been known

to have H1N1, H2N2, and H3N2,

so those are the
most common ones

that you'll hear
over and over again.

They're the most common
ones that are covered

in our vaccines as well.

Now, type B.

So type B infects humans only,

so it does not infect
animals at all.

There are two lineages of
circulating influenza B

for the past 20 years,

and those are called
Victoria and Yamagata.

So I talked about
the viral properties

in regards to hemagglutinin
and neuraminidase.

Now, I will go on and change
to talk about antigenic drift

and antigenic shift.

So these words sound
very similar,

and as a medical student,

and learning all of this,
they jumble up in your mind,

so I'll try and make them as
different as possible as I can

in using some analogies
moving forward.

But really, these are
important to understand

why we get outbreaks
of influenza

and why we get outbreaks
between continents of influenza.

So I'll first start
with antigenic drift.

So this is a similar influenza
virus that we saw before.

Instead, it's not opened,
it's actually closed.

So you have the hemagglutinin
and the neuraminidase

on the surface.

So like I had
mentioned previously,

influenza is an RNA virus.

With an RNA virus,
that virus is at risk

for having certain
types of mutations.

It doesn't do a good
job of proofreading

through any of the
viruses that it makes.

It does not do a
great job about it,

and so it can have
certain mutations.

It can result in
point mutations,

which is just a minor mutation

or a minor change that happens.

So when this happens on
those surface proteins,

with hemagglutinin
or neuraminidase,

what you get is a virus
that is closely related

but not exactly the same
as the initial virus.

So as you can see
here, the neuraminidase

changed from this circular
sort of flower structure

over to these squares overall.

So it's somewhat similar,
but definitely has changed.

This can occur with influenza A

and it can occur with
influenza B as well.

This is what leads to
seasonal epidemics.

So you have your virus,
it changes slightly,

but people still have
some immunity to it,

then that's when
you get your changes

and why the vaccine
may not be the best fit

or why certain people are
getting sick because of it.

So because it is closely
related, like I had mentioned,

there is some immunity

and so people do have
some cross-protection.

So there is...

Depending on how
big the change is

really depends on how much
protection you have circulating.

So we talked about the
drift, minor change

leads to seasonal epidemics,
occurs with influenza A,

and can occur with influenza B.

Now, we'll move onto
antigenic shifts.

So antigenic shifts,

we'll start with the
same influenza virus,

but now there's a major
change in the virus.

So it's not just a small
minor point mutation change,

it's a big change.

So really, you're
completely changing

what the virus looks like.

So in this case, the
hemagglutinin changes

from that blue color
to a yellow color

and it's a completely new virus.

This occurs only
with influenza A.

And this is what leads
to novel or new viruses

that can cause pandemics.

The other part of this
that is important to know

that, in order for these new
viruses to cause pandemics,

it has to be really distinct

from any other previously
circulating influenza viruses.

So the immunity to this new
virus has to be very low

or none at all for it to
actually cause a pandemic.

So how exactly does this happen?

How does an antigenic shift
or those major changes happen?

There's two ways
that have happened,

and I'll go over the
history of some of this

and some of the pandemics
that we've had in the past,

and which one fits into where.

But as I talked
about with influenza A

on the previous slides,
influenza A can infect animals

and it can infect humans,

so this is where the
shifts become important.

So I'll start off and say I
just made up these virus names.

They aren't actual names,
but we'll start with the pig.

So he has HpNp, the chicken
has HcNc, the duck has HdNd,

and then the human has HhNh.

So what happens is these
viruses normally circulate.

Some of the animals may have
symptoms, most of them don't,

so no one knows that they
actually have these viruses.

And then, somehow there's
a change in transmission

and it goes from the
animals to the human.

Okay, so this is not like,
let's use for an example,

the pig one, so HpNp,
is not something

that normally circulates
in humans but somehow,

someone was working
closely with pigs

or was exposed to the virus
when working with pigs

or eating pigs, and then
the human gets the virus.

This is something
that's called spillover,

so it's spilling over
from the animal population

into the human population.

So you may see that
word over and over again

when people talk about outbreaks
of respiratory viruses.

In order for these
viruses to go from the pig

to the human and to
actually infect the humans,

there's other things
that need to happen

in order for that virus
to cause pandemics

or to cause massive
outbreaks of them.

The virus itself needs
to be able to survive

and replicate in the human.

So it did a really good
job about surviving

and replicating in that pig,

but now it's in a
completely different host

with completely different
receptors for things.

And so that's really important
is if that virus can adapt

or change to actually
have that survival.

Like I had mentioned previously,

the human has to have no
previous or very low immunity

to this virus, otherwise
their body would take over

and get protected
with antibodies.

And then, in addition,
in order for it to pass

from one person to the next,
you need to have the virus

be able to be transmitted
from humans to humans.

So not only does it have
to be a spillover event,

there's all these other
factors that need to happen

in order to cause pandemics.

The pig is very unique
in this situation

because it has
respiratory receptors

for both the avian influenza,
so the bird influenza,

as well as the human influenza,

so it really facilitates

some of these interspecies
transmissions.

And where that becomes
important is this second method

of how antigenic
shift can happen.

It's something
called reassortment.

So reassortment means, if
we look in the middle here,

that the pig was infected
with multiple viruses,

so from the human, from a
previous pig, from a bird,

and then within the
genome of the pig,

it recombines all of
these genetic material

and makes a new virus.

Then that new virus can go

and combined again
with another virus,

and then create
another new virus,

and then it can
switch over to humans.

So this example here is what
caused the 2009 outbreak

with H1N1, referred
to as swine flu,

and so what happened
in this situation

is that there were two
different swine species

that were involved, so you
have the Eurasian swine,

which are located
in Europe and Asia,

you have your North
American swine,

which are located
in North America,

and then you have this
previous combination with human

and avian species.

So overall, there were four
different species involved

with it that really produced
this novel or new H1N1 virus.

So this is called reassortment.

The thing about reassortment

is that it doesn't
always lead to pandemics.

So reassortment can
happen, we may not know

that it's happening,
and as long as people

are not getting sick
or not dying from it,

we still wouldn't know.

So a lot of this
happens within animals

and we are unaware of it.

So this looks at the different
pandemics throughout history.

So we've had four total so far,

the first one starting with
the 1918 Spanish influenza.

So what is predicted
happened in that situation

was that first method
I had talked about.

So all of these are big
shifts that happened

that causes the major
mutations to cause a new virus

and cause pandemics.

With the 1918 Spanish
influenza, what happened

is that there were birds that
then transmitted their virus

that humans had never
seen before, to humans.

And then, it caused
a massive outbreak

where 50 million people died

with the 1918 Spanish influenza.

Then, with the second
outbreak in 1957,

referred to as the
Asian influenza,

this involved that reassortment,

so that second
method I talked about

where there is mixing
of the genetic material

to make these new viruses.

But this involved an
avian influenza strain

as well as a human
influenza strain

to cause H2N2 pandemic.

The third outbreak, here,

is the 1968 Hong Kong
influenza pandemic.

And this one also
had reassortment

of the avian influenza

and the human influenza
that exchanged material,

resulting in H3N2.

The last pandemic,
and the reason

why it's not on this
particular article

is that this article
was written in 2005,

and so the 2009 pandemic
was not on that one,

so we had previously
talked about that,

that was that
quadruple reassortment

with two different swines,
an avian, and a human

that then resulted
in this new H1N1.

For now, your next question,
I assume, is gonna be,

"Okay, well, what does this mean

"and can we predict when the
next pandemic is gonna happen?"

There are a lot of experts
that are trying to do

that exact same thing,

to try and predict what
exactly is gonna happen

and to try and come up
with antiviral medications,

to try and come up with vaccines

that can actually protect
against some of this.

Overall, experts are really
focusing on the avian influenza

and their concern about
the avian influenza

actually causing
the next pandemic.

And the reason for
this has to do with,

there's two current
strains of avian influenza

that have actually gone
to humans at this point.

The first one is
something called H5N1.

So H5N1 started to
become present in 1994

when they first noticed
that there was a new strain

in humans when
someone got very sick,

and they've been tracking it.

It's kind of spread throughout
different continents.

It's been present in Europe,
it's been present in Asia,

it's been present
in North America.

The thing about this one is it
causes very severe infection,

and the case fatality
rates are quite high.

So the case vitality
rates are 53%,

which means 53% of the people
that get this infection

are dying from the infection.

So for perspective-wise, the
normal seasonal influenza,

it varies a little bit
by year, but it's 0.1%.

Okay, coronavirus right now,
the novel coronavirus COVID-19,

is predicted to
be about 3 to 4%.

So when we're talking about
53% case fatality rate,

that is incredibly high.

The other interesting
thing about this H5N1

is that the median age is
very young at 20 years of age,

which is something
that has happened

with previous pandemics,
and I'll go into that

a little bit more when
we talk about immunity

moving forward, but
it's really hitting

the younger populations
with this type of virus.

The thing about this virus,
though, is that people

that have been infected,
they've been able to track

that they've had
exposure to ill poultry

about one week prior
to their onset.

So really, the control
of this virus has been

monitoring poultry and
mass killing of poultry

when they demonstrate
any symptoms.

In addition to that,
farmers are testing

a lot of their chickens or
poultry for this type of virus,

and then will proceed to kill
that whole area of chickens.

The second one that
also is concerning

is something called H7N9,
and this has caused outbreaks

within China.

The case fatality with
this one, as well,

is quite high at 30%.

The median age is older,
about 60 years of age.

But the reason why this
one is such a concern,

in addition to the
case fatality rates,

is that it is
resistant to Tamiflu.

So Tamiflu is the main
antiviral medication

we use to treat and to use
as prophylaxis for influenza,

and a lot of the other viruses

have not shown
resistance to Tamiflu.

That's why it's
so routinely used,

but this one in particular
has shown resistance,

which is really concerning

when you don't have a
lot of other options

to treat people with
for their influenza.

And so the CDC and the WHO have
actually labeled this virus

as the highest potential for
pandemic risk in the future.

Luckily, this virus
has incredibly poor

human to human transmission.

So people can get it from
interactions with a poultry

or a chicken that has
this type of virus,

but really, it's not
transmitting from one person

to the next, so there's no
further spread that's happening,

which is really important.

- Attendee: Is that
true of H5N1 as well?

- H5N1 has a lower human
to human transmission.

It's not as much.

There's about 860 cases
total from 2013 to 2018

that have been there,

so it's a pretty poor human
to human transmission.

But the concerning thing
with these avian influenza

is, like I talked about,
if they go through

any major antigenic shifts,

that can increase
their transmissibility

or make their transmission
from humans to humans better,

then that's where this
gets really concerning.

A lot of these patients end
up in intensive care units,

have very severe
pulmonary problems,

and then the high
case fatality rates.

So that's why this is
a very concerning area

in regards to influenza.

So I know I told you that
these words sound the same

and you may have heard me,
and they kind of blur together

when I talk about
drift and shift,

so I thought I would
give you an example

to take it home to try and
really give you a better idea

about remembering these.

So antigenic drift, imagine
you're on a lazy river, right?

So you're on the tube,
you're just drifting along,

you're drifting along, and
then you get stuck on the side

because there's a big bunch
of people that are coming by

and you get pushed
out of the way.

So your tube goes in a little
bit, shifts a little bit,

but in the end, you end up
in the same spot, right?

So you have a little
bit of a drift,

but you still end up
where you wanted to be.

This happens with influenza A,
and it happens with B,

and this is what leads to
your seasonal epidemics.

So if you think about it, when
you got stuck in that area,

you're close to the
people that you're around

in that local environment.

You can transmit that
virus in that point,

but then you go back to
your normal lazy river

once the crowding goes away.

Antigenic shift, you can think
about it as a gear shift.

So as you shift the
gear, you're ending up

in a different location,

or you're going in a
different direction.

So this is a major
change from your endpoint

that you initially had,

or your starting
point, I should say.

And this occurs with influenza A

and this is what
leads to pandemics.

All right, we talked about
the viral properties,

the surface antigens,
the neuraminidase,

the hemagglutinin.

We talked about the antigenic
shift and antigenic drift.

Now, we'll go onto transmission.

So I already previously
talked about the animal

to human transmission
and why that's important

in regards to influenza,

and now I'll focus on the
human to human transmission.

So I'll start with droplets.

So let's say you have
your infected person

that has influenza here,
and they're coughing,

and they're sneezing,
and everything is going

all over the place 'cause
they try to control it,

but as you know and you've
seen in some of those videos,

the snot goes everywhere,
and it's quite disturbing.

And with that, they're carrying
influenza virus particles.

So the influenza virus
particles get into the air,

and these are all different
ways that infectious disease

can be transmitted.

So with influenza itself, it
tends to be larger droplets.

So instead of these
smaller droplet nuclei

that you can see here, they're
really larger droplets.

So what that means is larger
droplets can't stay in the air

for a long period of time,
so you have to be quite close

to a person in order to
actually transmit influenza.

Some of the other things,
like tuberculosis,

which is airborne,
so these tiny nuclei,

they can stay in the air
for a longer period of time

and go further distances.

So let's put these
two people in a bubble

and let's say, "Okay, what
does that mean, really,

"in real time?"

The infected individual sneezes.

How close does the susceptible
individual need to be

in order to actually
transmit the virus?

And a lot of studies have
been done about this,

and what they have found out

is that it's between
three to six feet,

so it has to be quite close.

It's not always super close,
but it's a pretty close contact

within that three to six feet.

The other areas that
influenza has been shown,

although they're very
lower on the list

of being transmitted,
is direct contact.

So direct contact means
that you have direct contact

with that infectious particle,
so if you're sitting close

to that person within that
distance, and they sneeze,

and then you grab their
Kleenex, and now you have,

I don't know why you would
grab their Kleenex but,

[all chuckling]
you,

if it's a family member, you
don't think about these things,

so you grab their Kleenex,
now you have influenza virus,

potentially, on your hand,
and then we touch our faces

a lot, I don't know if
you guys have ever done

the experiments about how
many times you touch your face

within a day or within
a short period of time.

It's a lot.

And so, what you
would do is you have

those infectious
particles on your hand,

you then touch your nose,
you touch your mouth,

you touch your eye, and then
the virus particles are there.

Again, this is a lower
risk of transmission,

but it's still possible.

Indirect contact is
what we deal with a lot

in the hospital, so
indirect contact has to do

with the person that's
infected sneezes on their hand,

they touch an object, they
walk away, you would come up,

you touch that object
within a shorter time frame,

and you would then have
influenza on your hand,

and then touch your nose,
or your eye, or your mouth

in those situations.

So these are all
important to understand,

and a lot of studies
have gone into this

because of hospital
situations and precautions

that need to be preventing
hospital outbreak.

So I had to show
one gross picture

of,
[audience chuckling]

there's a lot of
'em on the internet,

but I had to show one gross
picture of someone snotty.

So now let's go through,
now that we talked about

how you can get transmission,
we have these infected people

with influenza, they can
transmit influenza virus

anywhere from one day
before their symptoms

to seven days after
their symptoms, okay?

So the one day before the
symptoms is something important

to keep in mind, because they
don't know that they're sick

at that point, and so
they can transmit it.

The highest transmission rate
is really three to four days

after the symptom onset.

So they cough or sneeze and
a susceptible individual

is within six feet of that.

So then what happens?

So once it gets
coughed and sneeze,

the susceptible individual
then gets that viral particle

in their nose, in their
mouth, in their eyes,

and then this happens.

So this is a picture
of influenza virus,

and you have epithelial
cells, which are right here.

Epithelial cells are cells that
line your respiratory tract,

so all throughout from
your nose to your pharynx,

so your throat, and then
into your respiratory system.

So influenza, what it
does is it attaches

to these epithelial cells.

So remember that glue I
was talking about before?

That's where these
become important.

So the hemagglutinin,
or that glue,

attaches to the sialic acid
receptors that are present

on epithelial cells.

So once it attaches to
those, then the virus

can then enter into your
system, and then replicate,

and go through the life cycle

that I talked about previously.

So we have these people,
the susceptible individual

gets the virus, the virus
attaches to the sialic acid,

it goes into the cell,
then about one to four days

after being exposed to the
virus, they develop symptoms.

So the one to four days
is when the virus enters,

and then symptom onset,

and so that's referred to
as your incubation period.

So how long it
takes for a person

after they've been
introduced with the virus

to actually have symptoms.

So relatively to some other
viruses, this is quite short,

and so people typically present
with symptoms earlier on.

So we talked about
droplet, now we'll go

onto some of the environmental
things that are important.

So here is a picture of the
world, and so what is important

in this picture is that
it's a study that was done

that looked at the peak
month of influenza,

so when influenza, during the
season, their peak month is,

and then how long it lasted for.

So we're very used to having
a set period of influenza.

It changes a little bit each
year, but most of the time

it'll last from
September to about March.

Some years it will
last a little bit later

depending on what's circulating
and what's going on.

With our peak time,
around January or February

in the United States.

But other areas of the
world don't have that,

or have different
environments that have it peak

at different times of the year.

So when we look at some
of these other places,

this is when their influenza
epidemics or pandemics peak,

is that in the
tropical environments,

they are peaking
around June or July,

lasting about the same duration
as our influenza season.

But the interesting thing
is over here in Asia,

they have these
semiannual peaks.

So they have two peaks
a year of influenza

instead of having
one peak like we do.

That has to do with
the environment.

So influenza really
likes colder temperatures

and low humidity.

So any time you alter
that or change that,

then influenza
doesn't do as well

with circulating in the air.

This is from 2013, so it
would be interesting to see

how this has changed, and
what will change in the future

with some of these climate
changes and global warming,

and what that will do for
influenza, both the seasons,

the duration of the seasons,
and when they actually peak.

So now I'll go onto immunity.

So I'll talk about population
immunity and vaccines.

So this is our
third concept here.

So we'll start with
this diagram here,

and the importance
of this diagram

really has to do with immunity,

and what the population
immunity is doing,

and how that relates to
outbreaks or pandemics.

So we'll start all the
way on the left here.

So we have an introduction
of a new virus.

So influenza A, HxNx, which
we've never seen before.

Okay.

So what happens after
that's introduction

is that it leads to a pandemic.

So you see your
disease incidence here,

so you get high disease rates,
and then those will fall

over time, and as those
fall, you see this antibody,

or the immunity to
that virus, go up.

And then you get
your next season,

which there is some immunity,

so some people have
created these antibodies

and can fight off
these infections,

and so, then you get lower
amounts of incidence.

And then as more of your
population is exposed

to this virus, you see
that your antibodies go up,

and then you see the rates
of disease go down overall.

So this middle range
is where we see

some of those drifts happen.

So those are those minor changes

that can affect and
still cause disease,

but really, people are
protecting themselves

with the antibodies they've had
from the previous infection.

So then what happens
again is that,

all the way on your
right-hand side,

there's an introduction
of a new virus.

So now we're introducing HyNy.

So even though we had
great immunity to HxNx,

that really doesn't help us
for this new virus that comes.

So with this new
virus that it comes,

you see a huge peak in your
incidence rates of disease,

causing another pandemic.

And then, over time, what you
see is the antibodies here

go along and start to go up,

and you see the same
sorts of cycles happen

over and over again.

So this is what you see
when you look at pandemics

throughout history and
that interpandemic era,

where you're seeing little
spikes but they're not as big.

It's because the population
has developed some immunity

to it.

I'm just gonna show
this in a different way

using our history to
help follow along.

So first I'll start with the
1918 pandemic, or outbreak,

the Spanish influenza
that happened.

So up top you have the
circulating influenza viruses.

Down below you have the
timeline of pandemics

or important things
in influenza history.

So in 1918, you see
that H1N1 arises.

It results in about 50
million deaths worldwide,

then H1N1 continues to
circulate throughout that time.

So as you follow
along the timeline,

you have your 1918 pandemic,
and then it circulates

until about 1947.

And then it has a slight
drift that makes it

a little bit different,
but still protected.

Then we get to 1957.

1957 is when we had
our second outbreak,

and that's when you
notice that H2N2 arises.

So you have your big peak
with no immunity previously,

and then H2N2 circulates
for a period of time.

Then you have your
1968 outbreak,

which you notice
that H3N2 now arises.

And then we get all the way
to 2009, where we notice

that there's this novel
H1N1, or the swine flu H1N1,

that came up that resulted
in 150,000 to 580,000 deaths

in the world.

What's interesting
about the 2009 outbreak

is that it really
affected people

that were less than
24 years of age.

And there was a lot of thought
when this initially happened,

like, "Why are all these
adolescents or college students

"that are healthy,
for college students,

"getting really sick
and not doing well?"

And what they noticed

is that there actually
was some similarity

between the H1N1
that circulated here

and the H1N1 that
circulated here.

That's why this arrow is there.

And so it seems like
the older adults

actually had partial
immunity to the new H1N1

'cause they had previously
been exposed to a similar H1N1

that provided cross-protection
or cross-immunity.

So with these
pandemics, you can see

there's certain age
groups that get affected

that aren't the typical
age group that you think of

with the highest rates of
incidence of influenza.

So we talked about
population immunity,

we talked about
antibodies circulating,

now we'll go onto
influenza vaccine.

So we'll start with
our virus here.

What some of you may have
noticed on the previous slides

is there are these areas that
are called antigenic sites

on this hemagglutinin,
and these become important

when we talk about
influenza vaccine.

So how does influenza
vaccine work?

What it does is
your body is exposed

to either a weakened or
killed form of the disease,

and then your body
creates these antibodies,

which are present here
after being exposed to it,

and then these antibodies,
let's say you got your flu shot,

you developed your antibodies,

and then you got exposed to
influenza, unfortunately.

And what happens
is these antibodies

go to these antigenic sites
and actually clamp onto them.

So we're talking
about these antibodies

that were in your
system go to the virus,

the outer portion of the
virus, and go on top of them.

And so what that does,
is our previous picture,

is it blocks the virus
actually being able to attach

to those sites.

So the virus is unable to
attach the sites of the cells,

and so they can't
enter into the cells,

and then your body
mops up this virus

through other
immune system cells,

and is able to get rid of
it so you don't get sick.

So that's how the influenza
virus actually works,

is it really blocks
this attachment part.

So the influenza vaccine,

we'll talk about
the 2019, 2020 one,

these are the different viruses.

You don't have to
read all of them,

just know that there's
two influenza A viruses

on there, and there's two
influenza B viruses on there.

All of the other stuff

really is just really
specific virology names

and what specific virus
they put into the influenza.

But you can see here
that the first one

was an H1N1-like virus,
the second was an H3N2,

and then you have your
Victoria and your Yamagata.

The stars next to
those first two ones

is what changed from the
previous year's vaccines.

So every year, at the end
of the influenza season,

a ton of experts get
together and try to predict

what they think is gonna be
circulating the following year.

And what they predicted for
this year are these four.

It's still too early to know

exactly how effective this is.

There's varying rates
between the virus strains.

It's probably about 30 to 50%
vaccine effectiveness this year,

which is pretty typical
of the influenza vaccine.

But these first two
are new ones this year.

So the important thing to
know and the important thing

that I like to tell patients

when we're talking
about influenza vaccine

is you're 50 times
less likely to get sick

from influenza
compared to someone

who doesn't get the vaccine.

So I feel like this is
an important concept

that we don't talk
about very much.

And, in addition, not only
do you have 50% less likely,

if you do get an
influenza strain

that's not one of
the ones listed,

there is some cross-protection.

So you can have less severe
disease even if you get exposed

to an influenza virus that
isn't covered by the vaccine

that year.

So now the vaccine
impacts on influenza.

So this is the most recent
updated that the CDC has

about what the actual vaccine
is helping to prevent.

So in the year of 2017 to 2018
in the United States alone,

it prevented 5,700 deaths.

It prevented 91,000
hospitalizations.

Does anyone what this
is, the picture of?

Some stadium, it's Lambeau.

So Lambeau Field can
hold about 81,000,

so we're protecting 10,000
more than what Lambeau Field

can hold in hospitalizations.

In addition, we protected
3.2 million medical visits

and 6.2 million
illnesses overall.

So we protected over an entire
state of Wisconsin population

with illnesses with the vaccine.

So that's quite impressive
of something that we can do

and why a lot of medical
providers really push

for influenza vaccine.

And this is just in the United
States, it's not worldwide.

The rates are much higher when
you look at the whole world.

So we talked through
these three concepts,

which I think are
important in influenza,

and to help you understand
some of the other things

that can happen in other
respiratory viruses

that are important, why we see
these pandemics or outbreaks.

So with influenza, we talked
about those viral properties

that are important for the
structure of influenza,

how it gets into your cells,

and then why it causes
epidemics and pandemics.

And then we talked about the
transmission with droplets,

and some other transmission
that can happen

as well as the environment
and any climate changes

that may affect that.

And then the last concept
had to do with immunity,

which is important overall,
about your population immunity,

so overall, who's being covered,

and then also the
vaccine itself.

So these are the important
things to take away,

and why pandemics happen

is a change in each
one of these concepts

can really lead to a
big outbreak of things.

So viral properties,
when we get new virus,

or a novel virus, and then that
virus is easily transmitted,

and then the population
has no previous immunity,

that's when we get really
big outbreaks with viruses.

So I'm gonna talk briefly
about my specific research.

I was just giving you a
rundown about influenza.

So my research really
has to do with the impact

of respiratory
infections in children,

and why I care about
that, and why I think

that that's important is
a lot of these numbers.

So overall, $40 billion
is spent per year

on non-influenza respiratory
infections in children.

So those rates skyrocket

when you actually include
influenza into those accounts.

It also accounts for greater
than 45 million missed days

of work and 22 million
missed days of school

because of kids being sick,
parents needing to leave work,

or parents themselves being
sick, adults being sick.

The other interesting
thing is down here.

So the $2 billion per year
is spent on cold remedies.

So this is out-of-pocket money

that we are spending on
cold remedies, overall.

So really where I found this gap

in the respiratory infection
research in children

has to do with, we
have clinical trials

for some of these
symptomatic treatments,

we have clinical
trials trying to use

some of these antivirals
in certain type

of respiratory viral infections,

but really, the
measures that they use

are not consistent
between the trials,

and they're not validated.

So they previously haven't
been shown to be valid

in pediatric patients with
acute respiratory infections.

So what this means is
that it's really hard

to compare clinical
trials in children

when they're trying
to see what helps

improve their
respiratory infections

or helps to cure their
respiratory infections.

Then, it's also challenging to
interpret what this data means

when they use measures
that haven't been validated

or haven't been
researched previously.

So Wisconsin Upper
Respiratory Symptom Survey

is something that was
developed by Dr. Bruce Barrett,

who is a part of the
Department of Family Medicine

and Community Health.

He developed it in the 2000s
and it was focusing on adults.

So it's an illness-specific
quality of life instrument

that was used to assess
the negative impact

of acute upper respiratory
infections in adults.

It's been used in various
different clinical trials,

and really, what's happened
with it is it's really exploded.

So 150 institutions
around the world

in 35 different
countries use this survey

to help with their
clinical trials,

their observational trials, and
any pharmaceutical companies

that have picked
this up as well.

It's translated to multiple
different languages

to be used in these
different countries.

So what I am doing right
now is taking that framework

of the Wisconsin Upper
Respiratory Symptom Survey

and trying to validate
it in pediatric patients.

So it was validated and proven
to work in adult patients,

but as we all know,
children are very different

than adults in many
different aspects.

So what I'm trying to
do is really assess

their symptoms and
their quality of life,

and how that impacts
their scores overall,

and what that means with
the overarching structure

of the actual form.

My goal is to use it
in future clinical

or observational trials
focusing on children

in an outpatient setting with
acute respiratory infections.

There is a lot of research
being done about children

that are hospitalized,
children that have asthma,

or infants with acute
respiratory infections,

but this part with
the outpatient setting

with acute respiratory
infections,

there hasn't been
as much research.

So where I am now with things is

I completed the administration
to all the participants

in my study.

The analysis shows that it
holds together quite well,

and it's valid and reliable,

so now I'm thinking about
where do I fit this in

with different clinical trials
and where do I go with this

at this point?

These are all of the people
I would like to thank.

So as you know, there's
a lot of people involved

in a lot of this work.

With the WURSS Kids,
these are all the people

that have helped me
get to where I am,

and then my mentors as well.

So I'm a part of two
different departments

at the University of Wisconsin,

so I'd like to thank the
University of Wisconsin

Department of Pediatrics

and the Department of Family
Medicine and Community Health,

and then the Wisconsin
Survey Center

helped to put together the
WURSS Kid Symptom Survey

that was used and validated.

So thank you,
guys, for listening

and taking the time
out of your night.

[audience applauding]