Good afternoon, everybody.
We are going to go ahead and start.
People are still kind of trickling in.
Apologies for the food being late,
but it usually makes people happy to have food,
so we like to be able to set the stage with that.
So it is my pleasure to be here this afternoon
to introduce our university scholar presentation.
We are 42 years into University Scholars
at the graduate college,
and this is our third speaker of four for the year,
and, obviously, you're welcome to get refreshments
and you can get them and go back out there
if you need to during the talk or not.
We don't mind if you do that.
So the purpose of the University Scholar Award
is to recognize excellence
and, basically, history and longevity
and really doing fabulous research
in creative works and scholarship.
So, today, in that vein,
we recognize Professor Anne Dixon,
Somewhere over my vision there,
who is, I have to read these,
the interim chair of medicine,
the director of the Division of Pulmonary
and Critical Care of Medicine,
the director of the Vermont Lung Center,
and a professor of medicine.
Dr. Dixon is originally from England
and moved to the United States
after completing her undergraduate studies
at Cambridge University
and Medical School at Oxford University.
She completed residency training in internal medicine
at Johns Hopkins in Baltimore,
and a pulmonary and critical care fellowship
at the University of Washington
before joining the faculty at UVM in 2001.
Her research career is focused
on clinical and translational studies
to understand mechanisms linking obesity and asthma,
and she has led basic translational
and clinical trials on this topic.
Dr. Dixon has over 100 publications
and has led a number of international workshops
and symposia.
She was the editor of the first book published
on obesity and lung disease,
and is currently working on the second edition of that book.
She has been recognized for this work
with an American Thoracic Society Achievement Award
and honored by the Asthma and Allergy Foundation of America
New England chapter
with a Champion Award for her contributions.
In addition to her research contributions,
she recently served on the expert panel
updating the national asthma guidelines
for the National Heart and Lung and Blood Institute.
She also chairs the Scientific Advisory Committee
for the American Lung Association
and the American Board of Internal Medicine
Pulmonary Board Certification Exam Committee.
There's a lot more we could tell you about Dr. Dixon,
but we always like to stop
and just share something light
about our University Scholars presentations,
and for Dr. Dixon, as we've learned from a colleague,
that she rode for Oxford University
during her days as a medical student
and I mean rode, like, boats, not horses.
-(crowd laughing) -Very impressive.
And with that,
I'm pleased to now introduce Professor Dixon
for her inaugural University Scholars lecture entitled
"Fat and Flow:
Elucidating the link Between Obesity and Asthma",
and she'll take questions at the conclusion of the talk.
(crowd applauding)
Well, thank you, Dean Forehand,
for that very lovely introduction
and thank you, all of you, for being here today.
This means a lot.
It really does.
And so, what I thought I would start off with
was talking a little bit about my background,
because, I think, when you hear it from Dean Forehand,
it all sounds very straightforward
and I know for the young people sitting in the audience,
it sort of sounds like,
"Whoa, she really knew what she was doing,"
and that might not be the exact truth.
I'll explain to you how I got to my interest
in obesity and asthma,
and then I'll tell you about
the research that we've done
to try and elucidate the pathogenesis of this disease,
and a lot of work we've tried to do here
on how to treat this disease,
and a lot of people who actually do the work
are sitting here in the audience,
so thank you for coming.
So I'm originally from a town
in the southwest of England called Plymouth.
It's an area which is a beautiful part of the country,
has lots of dairy farms and lots of tourists.
Sounds familiar, doesn't it?
One of my early memories, actually,
is of my grandfather happened to auction off
the animals and the equipment from his farm.
He had really bad farmers' lung disease,
which probably is one of the reasons
I ended up in pulmonary medicine.
I was lucky enough to go to two very beautiful places
where I did a little bit of work
and a lot of rowing actually.
That's something I usually try and hide from people,
but it was a glorious time.
And after internship, I did something
to my mother's horror, actually,
I married an American.
-(crowd laughing) -And so, it wasn't like
I was on a trajectory
to go from Oxford to Hopkins by any manner of means,
but I married an American,
and so, the deal was,
if I moved to the United States,
the moves thereafter would be mine,
which is important to make that sort of deal.
So he was actually finishing up law school
in Ann Arbor, Michigan,
and so, I ended up in Ann Arbor
for nearly a couple of years,
doing exams, including the English language test
and also worked in a lab looking at retinoic acid receptors.
But then I got my exams,
we found a place where both of us could work,
and so, we moved to the Baltimore-Washington area
where I did residency at Hopkins,
which was a wonderful place to work,
and I still have friends and colleagues from Hopkins
that I work with today.
But, you know, for a girl from Plymouth,
the Baltimore-Washington area is not necessarily
where you wanna spend your entire life.
And all the moves were mine, right?
And so, we moved to Seattle, Washington,
which was a fabulous pulmonary and critical care division.
I actually worked in a lab
at the Fred Hutchinson Cancer Research Center
for my research,
looking at post bone marrow transplant lung injury,
the same lab as Dr. Dan Weiss.
The two of us have been together for a long time.
(audience member speaking faintly)
(Dr. Dixon laughing)
And that research was going really, really well,
but I kind of got to my fourth year.
I got a great score on an NRSA,
but, you know, I had a two and a half year old,
I was pregnant, and I was like,
"How does anyone do academic medicine
and take care of their family?"
And so, I did a complete 180.
My poor husband's getting whiplash by this stage,
but we moved back to the east coast,
because that's where the family is
and we ended up in Chapel Hill, North Carolina.
I actually took a job in private practice.
Well, I lasted two weeks
before realizing that was the biggest mistake of my life.
I was doing outpatient pulmonary
and it was great lifestyle-wise,
but I really, really missed academic medicine,
and so, I called back to my mentors in Seattle who said,
"Well, Polly Parsons has just moved to Vermont
and she is hiring so you should give her a call."
So after about a year,
I ended up here at the University of Vermont
and I have loved my time here.
But I was originally hired as a clinical scholar,
so pretty much as a clinician.
But I was really lucky,
and I was lucky,
because Charlie Irvin and David Kaminsky,
at that time had just started working
with the American Lung Association
Airway Clinical Research Centers,
and this has really been a very important part of my career.
I think there were 19 centers at that time, right, Charlie?
We were the only one in New England
and I started working with them,
and I was working on a project on sinus disease and asthma,
and, actually, I got my K23 doing sinus disease and asthma.
When there was a study
that Charlie was actually the PI on
that had a really unusual finding.
This was a study where,
if we treated people with Theophylline to improve asthma
and there were three really important findings
that really caught my interest.
One of which was over 50% of our participants were obese,
so a really high prevalence of obesity at a time
when in the nation, it was about 30% of the time.
People with obesity tended
to have much worse asthma control.
And when we put them on Theophylline,
we made them even worse.
So, if you were skinny and we put you on Theophylline,
you had fewer exacerbations,
whereas if you were obese and we put you on Theophylline,
you got worse, and this really sparked my interest.
We still haven't entirely figured out
the reason you get worse on Theophylline,
but more of that later.
This was, I think, the second paper that came out
that suggested altered responses
to medications in people with asthma
and there've been a whole bunch since.
So I thought, "Well,
obesity seems to be making asthma worse.
Where do you go from here to figure it out?"
Well, we work in a really, really collaborative place.
And so, I went to my bariatric surgeon colleagues
and a big thank you to them.
Dr. Forgione and Dr. Abarjaz have put up with me for years,
and we did a study in bariatric surgery asking,
does weight loss improve asthma control?
A really simple question.
Patients lost a lot of weight,
so their BMI went from, on average, 51 down to 37,
their asthma control improved very, very significantly.
So the asthma control score here
before surgery was 1.55.
1.5 or above is considered poorly controlled asthma.
0.75 or below is considered well controlled asthma.
So, they went on average,
from having very poorly controlled asthma
to well-controlled asthma.
Their FEV1/FVC,
the ways we measure lung function, also improved,
so things were looking at a lot better.
But one of the ways that we really try and figure out
what is going on with asthma,
asthma, the airways are inflamed, they're twitching,
and so, we wanted to see
whether, how reactive the airways, if that changed.
And that was kind of a more nuanced story.
Because we found that some patients,
their airway reactivity really improved.
And the way that you look at this graph,
we measure airway reactivity.
Oh, I completely lost the pointer.
So on the Y-axis is looking
at the concentration of methacholine required
to produce a 20% fall in your lung function,
so the lower you are on the Y-axis,
the twitchier are your airways,
and so, there was a group of people
who had non-allergic asthma
who went from having very twitchy airways
to getting much better.
But there was another group,
people with early-onset allergic asthma
who, their airway reactivity
did not seem to change much at all,
suggesting for the first time
that there was at least
two phenotypes of asthma in people with obesity.
Now this is sort of, you know,
I'm showing this complicated graph.
Really, a couple of patients really brought home to me
what these two phenotypes were.
Because, in this non-allergic,
there was a woman who developed asthma in her late thirties
the year before she underwent bariatric surgery.
She was in the ICU six times,
six times with asthma exacerbations.
She went through bariatric surgery, she lost weight,
she got off all asthma medications,
so really transformed her asthma.
And in the allergic group,
there was a woman I ran into at the coffee thing
on the second floor over there one day
and I said, "How are you doing these days?"
And she said, "Well, you know what Dr. Dixon?
I feel much better.
I can walk up the stairs.
I don't wheeze, I don't cough,
but every time I go to my daughter's house with the cat,
I get wheezy again."
And so, this really threw it into sharp relief
what these two phenotypes of asthma were.
And so, we described these two different phenotypes
and I like to think of them as asthma consequent to obesity,
and asthma complicated by obesity,
and more, both of these.
So, the first thing,
we'd identified this form of late onset non-allergic asthma
and the obvious question is,
why on Earth are these people developing asthma?
What is going on?
Now for those of you that don't think about asthma,
I can't imagine why you wouldn't,
but asthma is an inflammatory disease of of the airway.
So, on your left,
you see a nice, wide open airway,
and on your right,
what you see is a mucus filled, narrowed,
and planed airway,
and this is driven by certain cytokines,
what we call the Type 2 cytokines,
IL-4, IL-5, IL-13,
increased mucus production,
gunk in the airways,
eosinophilic mass cells.
So asthma is an inflammatory disease.
Well, you know what?
Obesity is an inflammatory disease, right?
We know that.
And so, this is a photo micrograph
that was for a patient
before and 12 months after bariatric surgery.
And the photo micrograph there on the left,
the blue is nucleus staining,
the red is CD68 staining for macrophages,
and what you can see is, that before bariatric surgery,
or at the time of bariatric surgery,
this adipose tissue is infiltrated
with these pro-inflammatory macrophages
that throw out high levels of cytokines
such as IL-6 TNF-alpha.
12 months later, in the same patient, it's less cellular.
The adipose sites themselves are actually smaller.
So, fat in the setting of obesity
is a much more pro-inflammatory tissue.
And so, I came up with what seems like
the obvious hypothesis, right?
So asthma is an inflammatory disease.
So my hypothesis was
that inflammation associated with obesity
increases airway inflammation.
So we did the experiment,
and what we had done was,
we'd done bronchoalveolar lavage
on these patients at the time of bariatric surgery,
and on the left panel,
what you're looking at here is,
on the gray is controls at the time of bariatric surgery,
the dark gray is asthmatics
at the time of bariatric surgery,
and the black is the asthmatics 12 months later.
And what you can see from a bunch of these
inflammatory cytokines, IL-8, NCP, TNF,
they actually increase after weight loss,
so completely opposite my hypothesis.
and the other thing that we did
was we took out lymphocytes and peripheral blood,
so we took out CD4 positive lymphocytes
and we just stimulated them in vitro with CD3 and CD28,
and the panel on the left shows a composite
from controls at time zero,
asthmatics before bariatric surgery,
and then asthmatics 12 months after bariatric surgery,
and lo and behold,
you stimulate the lymphocytes
of patients 12 months after bariatric surgery,
and they produce much higher levels of these cytokines.
So completely opposite of what I thought.
Matt Poynter and Jen Ather have actually shown this
in a much more elegant way
in a house dust mite mouse model
where they used low fat, lean mice,
high fat, obese mice,
and mice that were switched from high fat to a low fat diet.
And what they did was,
they took the spleens out of these mice,
much easier to do in mice than to do in humans,
and they stimulated it with house dust mite
and what you can see is
the high fat diet mice produced much lower levels
of the cytokines that they measured,
including IL-5, IL-13, and IL-17.
So, quite contrary to my hypothesis.
Obesity was not increasing allergic inflammation
by any manner of means.
But what was also really interesting
was when we looked at the adipose tissue
of these asthmatics, compared to obese controls,
the adipose tissue, the visceral adipose tissue
of obese asthmatics is more inflammatory.
It produces higher levels of leptin,
it's got more macrophages,
and it's got lower levels of things like adiponectin
which has anti-inflammatory effects.
So we are seeing inflammatory disease in the adipose tissue,
but not the airway.
And, actually, when we looked
at visceral fat leptin expression, you can see,
the more leptin you get, the twitchier your airways.
I don't know if that's causation,
but that's pretty interesting.
And this is since been supported
by numerous other publications.
A group in Australia did a very similar study to us
and a group out at UCSF
has done a lot of works showing circulating IL-6,
which is produced predominantly by adipose tissue,
is associated with poor asthma control
and increased asthma exacerbations.
Based on that, they're doing a a study of anti-IL-6.
I personally think the IL-6
is just a mark of metabolic dysfunction.
So, what is the adipose tissue doing?
Well, Matt Poynter has done a lot of work
trying to sort this out.
And he found, when he takes conditioned medium
from adipose tissue
and puts that on antex mouse airway epithelial cells,
it modulates cytokine production perhaps not surprisingly.
The other really interesting thing in this paper
that they published back in '21 is, actually,
the mouse epithelial cells from obese mice
produce different levels of cytokines
than the epithelial cells from the lean mice.
So it's not just that the adipose tissue has changed,
but the airway cells themselves have changed
in the setting of obesity.
So a lot of work still to sort of figure that out,
but at the same time we were really trying to understand,
to inform treatment,
what are the physiologic functional characteristics
of this late onset non-allergic asthma.
Because how are we gonna figure out how to treat it
if we don't know?
Well, we had done a study way, way back
where we had looked at lung elastance,
you know lung stiffness before and after bariatric surgery,
and the white here is obese controls
before bariatric surgery.
The light-gray is obese controls
12 months after bariatric surgery.
The middle-gray, I guess I'll call it,
is asthmatics before bariatric surgery,
and the really dark gray is asthmatics post weight loss.
And what you can see is that the asthmatics
have really high lung elastance,
compared to the obese control
and that's when controlled for weight.
We since just had another study
that's been accepted for publication
where we found that this is a little more nuanced.
And so, we looked at response to our Methacholine
in our obese controls, and our obese asthmatics.
And we were able to identify
there is a subgroup of these obese asthmatics
when we give them Methacholine,
and we look at their lung reactants.
Their lung reactants is measured by airway
under the curve of the reactants,
goes to really, really high levels.
They have really, really stiff lungs
when you give them Methacholine.
There's a group of obese asthmatics
that don't look that different than obese controls.
And, actually, when we went back
and we looked at their lungs
before we gave them Methacholine,
you could even then pick out this group
that have got stiff lungs at baseline,
which just gets worse with Methacholine.
Well, so what?
Well, there's a couple of things
that are really interesting about this,
is, one, you cannot detect,
which this subgroup is
by doing conventional lung function test.
You have to use a technique that we call oscillometry.
So there is a group here with developing really stiff lungs
and these really stiff lungs
are associated with increased symptoms of chest tightness,
increased wheeze,
and in this group, they also had more asthma exacerbations
in the 12 months before we studied them.
So there is a group of people
who are coming to us complaining of a lot of symptoms.
They're wheezing,
they've got chest tightness,
they're getting lots of exacerbations,
their lung periphery is really, really stiff,
and we have got no good way of detecting it
unless we do this technique called oscillometry.
But what is causing this?
And so, it looks like the periphery of their lung
is getting really, really stiff.
And so, we had this obvious hypothesis,
is that their airways were collapsing down.
And so, we recruit four groups,
we recruited lean controls and asthmatics
and obese controls and asthmatics,
and we did an imaging study
with our help from radiology here,
Brian Walsh, and a very talented postdoc
who was working with us at the time,
and we did CTs.
This is an obese control at the top on full inhalation,
and what you can see here is the left main stem bronchus,
right main stem bronchus,
beautiful black lungs during inhalation,
you breathe all the way out
and the airways completely disappear.
This is not normal.
So the airways are not supposed to completely collapse down
and this is an obese control.
There's nothing wrong with this patient.
If you look at an obese asthmatic,
beautifully patent left and right lane stand bronchus,
black lungs,
they exhale the airways disappear
just like the obese controls do,
but you also get the sense
that their lungs are a little blacker,
and so, we published that this tendency of the airways
to collapse, this Tracheobronchomalacia ,
or as it's called now,
expiratory dynamic airway collapse,
seems to be related to BMI,
it's not related to obesity
and I think it's likely leading
to an epidemic of Tracheiobronchomalacia.
But it's not explaining our asthma.
But what is happening is,
when we look at the characteristics of the lung,
so this is whiteness of the lung,
which is sort of complete collapse
measured by high attenuation area
versus blackness of the lung,
which is air trapping,
and you see the obese controls,
compared to this LONA group,
their lungs are not as white
and they're blacker, so they've got more air trapping,
and age was a really important co- variant of this.
And another postdoc working with Jason Bates and myself,
Swati Batwa was the first author on this study.
And this, I think, is one of the reasons
we're seeing this as patients get older,
why age is an important co-variant, we don't know.
And so, what's causing this tendency?
They're developing this air trapping, we don't know.
A lot of different theories,
some of them we're trying to work on
is it increased smooth muscle tone?
Is it increased airway liquid?
Is it abnormal surfactant function?
Watch this space.
So though we don't know what's causing it,
I'm a clinician, I'm very pragmatic.
I do think this tells us how we might be able to treat it.
So, if they're collapsing down,
one way that we might be able to treat it
is by giving positive airway pressure.
And so, we recently published a study with Jason Bates
in which we gave Methalcholine
to some of these late onset nonallergic asthmatics,
and we measure the development of elastance in black
with no positive expiratory pressure
and in red sort of with this positive expiratory pressure,
so it gives you a little bit of breath assist if you like
when you breathe out.
And you can see the elastances don't get as high
in these obese asthmatics,
and, actually, this correlates with lower respiratory rate,
and increased tidal volume,
suggesting that positive expiratory pressure
may be a great intervention for these folks.
And so, we're actually just completing a study right now,
looking at the efficacy
of continuous positive airway pressure
for these folks giving it at night.
That seemed like a great idea.
Anybody hates sleeping with CPAP though?
So maybe not,
but another thing that we have just started working on
is giving us CPAP with exercise.
So these people we think are developing air trapping
and it's really difficult.
They are not gonna show you,
they don't recruit the lung very well.
And so, if you're over at the Fanny Island one day
and you see a bunch of people walking
up and down the hallway with CPAP machines on,
they are part of our study.
(audience giggling)
So that's this late onset non-allergic asthma of obesity.
What about early-onset allergic asthma?
Because it's really much complicated by obesity.
This is not the same as lean disease.
And for clinicians out there, if you look at these people,
they tend to have lower levels of eosinophils
in their sputum, lower levels of exhaled nitric oxide,
though these eosinophils get stuck in the airway wall.
And so, we've been working on that for a number of years
and one of the reasons I got into this
was because of an experiment we did
with Albert Vanderbleek in pathology.
And Albert got us to do an allergen challenge.
And what we did was we took people
who are allergic to house dusts mite,
and we stuck some house dust mite up their nose.
Right Olivia, we do it all the time.
And so, the lean asthmatics are here in the black
and the obese asthmatics are here in the red.
and we measure the cytokine production
before, 15 minutes after, and 24 hours after
we've given the allergen challenge.
And much to our surprise,
at this dose of house dust mite,
we saw that they developed high levels of cytokines
such as IL-13, I think this is IL-33, IL-13,
and he also measured slightly higher levels
of ATP and hydrogen peroxide in the airway,
markers of suboxone stress.
Albert went on to show, he was very interested
in this NADPH oxidase in the airway, DUOX.
Albert went on to show that the obese asthmatics
appeared to have higher levels of leptin
in the epithelium and higher levels of oxidation of cystine.
So what he did here was,
he measured oxidized cystine using a DCP-Bio pull down
and detecting the strapped evidence.
So black, sort of all these proteins
where the cystines are oxidized.
And you can see this is much greater in the obese asthmatic
than in a a healthy weight asthmatic
or in the healthy controls.
And he went on to do some elegant work
using an epithelial knockout of DUOX
to show that if he knocked out DUOX
from the airway epithelium
you could improve this airway reactivity
in this obese allergic mouse model.
And, actually, leptin appeared to increase expression
of DUOX in the airway.
(phone ringing)
(electronic voice speaking faintly)
I'm just glad that's not me.
(audience laughing)
And so, in another work there,
Yvonne Janssen-Heininger's group has been doing.
Yvonne has really done some groundbreaking work
looking at alterations in glycolysis in the airway
in lean asthma.
So Pyruvate kinase is the terminal enzyme
in the glycolytic pathway.
And there are various Pyruvate kinase M2
is altered structure of the Pyruvate kinase.
They can form dinas or they can form tetranus,
that's the word!
Thank you, I'm so glad you came over.
And depending on the confirmation,
determines whether this goes into oxygen phosphorylation
or goes into form lactate and increased airway inflammation.
And Yvonne's group has shown
that that's really important in lean asthma,
and what Alison Manuel did
when she was working in Yvonne's lab,
was showed that there's also dysregulation
of this Pyruvate kinase M2 pathway
in obese allergic asthma.
And they use pharmacologic approaches,
and, apparently,
we're no longer in communication with the company.
But they also use genetic knockouts to probe this pathway.
Genetic knockouts are much harder
in humans so advanced.
So, it's gonna make it harder to pursue.
Our own group has also found evidence
of our increased airway oxidative signaling in the airway
and this was worked done by Brittany Duchene
when she was a fellow with us,
and Sarah Caffry I think is here somewhere,
who's now in the second year of medical school,
and we had looked at,
I use the nose a lot.
So this is 8-isoprostanes and nasal lavage
of lean, overweight, and obese asthmatics.
And you can see higher levels of these oxidative markers
in these obese asthmatics.
And this suggested a way
that we could actually begin to get at this pathway,
because we hypothesize
that some of these increased airway oxidative stress
could be coming from abnormal mitochondrial production
of reactive oxygen species.
And this is work that's been led very much
by Ravi in our group and Vikas Anathy,
and this is using, on the top we've got low fat diet mice,
given PBS, house dust mite, or given house dust mite
plus this mitochondrial targeted antioxidant, Mitoquinone.
And at the bottom, you've got obese mice,
PBS, house dust mite, given Mitoquinone,
and what you can see here is
one of the features of obese allergic asthma
that I told you about,
where the eosinophils get stuck in the airway wall.
And Ravi was able to recapitulate that feature,
and when we gave this mitochondrial targeted antioxidant,
it seemed to really help with this airway eosinophillia
and many of the other markers of this obese allergic asthma.
I'm glad Ravi's here,
because if I misquote he can always interrupt me.
But then he went to try and identify targets
that could have been a susceptible to oxidation,
and so, he used again this DCP-Bio pull down method
which lets you identify oxidized cystine residues,
and we're working with the proteomic facility here
in lean versus obese mice.
He was able to identify proteins
that were oxidized on the cystine residues in the red.
It's up-regulated by house dust mite,
decreased by Mitoquinone,
and in the green is just up-regulated by house dust mite,
and you can certainly get the impression
in the setting of obesity,
we've got increased upright oxidation of more proteins
than in the lean setting.
And when he looked to see
what was particularly getting oxidized
in the setting of this obese allergic asthma,
he identified a number of proteins
that are particularly involved
in protein folding in the ER,
suggesting that maybe targeting ER stress response
might be efficacious for the treatment of obese asthma.
Now I'm terribly pragmatic, right?
I wanna treat my patients, and so, at the same time
we've got a trial that's ongoing at the moment.
So MitoQ is available over Amazon
-as an anti-aging supplement. -(audience laughing)
So, just so you know,
but we're actually using this at the moment
to treat obese asthma.
Olivia is doing a fabulous job of recruitment.
We're working with Duke,
who are not doing such a fabulous job of recruitment,
but we'll get there.
So, what other treatments do we have for obese asthma?
And I'm gonna share with you a couple of trials
that we've recently published
that shown some really interesting results.
So one study that we just completed was using roflumilast,
roflumilast is a phosphodiesterase score inhibitor
that's FDA approved in this country
for the treatment of chronic bronchitis
with recurrent exacerbations.
It's not approved for asthma,
but I thought I was really smart,
because a side effect of this drug is weight loss.
There's actually been a study suggestion
that improves glycemic control.
It has some, perhaps, GLLP-1 receptor agonist type effects,
roflumilast does have some efficacy
in many people with asthma,
though it's never been FDA approved.
It's been studied in obese mass models of asthma.
And, actually, there's been case reports
of using it in obese people with asthma
and reporting improved asthma control.
And so, we got funding for the NIH
to do a study at six centers,
where we randomized people to our roflumilast
versus placebo, and what we found here,
the yellow is patients on roflumilast.
The blue is patients on our placebo.
And you can look at change in asthma control score,
and it doesn't take a statistician
to tell you that this was a pretty disappointing result.
We did not improve asthma control.
That was pretty disappointing.
There was a little silver lining in this.
There was a secondary part of this analysis.
We were interested,
whether inducing weight loss might improve asthma control,
and so, a three point reduction in an asthma control score
or increase in the asthma control score
is a clinically significant improvement in asthma control.
And so, we saw a clinically
and statistically significant improvement
in asthma control in people who lost at least 5% weight.
Actually, this included both people who were on roflumilast
as well as placebo.
We sold this as a weight loss trial.
So I think some people really tried to lose weight.
So this was really encouraging.
However, when you're doing a clinical trial,
you have to look at risks and benefits as well.
So we looked at harms
and there we had a real wake up call.
So if you look at SAEs in patients on placebo, zero.
SAEs in patients on roflumilast, six.
The DSMB sort of had a field day with this,
particularly, because we looked at exacerbations
from diary cards,
and so, got this result after completion of the study.
And so, if you look at urgent care visits
for asthma in patients on placebo versus roflumilast,
you'll see that Ramsey is not gonna want me
to put patients on roflumilast
with crowding in his ED at the moment.
So we actually made them worse.
Why? We don't know.
Carolyn is currently working doing some proteomics
and we've gone another molecule
I think that we're gonna go after
looking at the serum to see why we made them worse.
So roflumilast did not benefit asthma control,
it increased the risk of asthma exacerbations,
but 5% weight loss may be helpful.
And so, that leads us to lifestyle interventions.
Now we did a lifestyle intervention
and we were lucky enough to be able to work with Jean Harvey
here in the School of Nutrition.
We actually did a six month online weight loss study.
We did it 40 participants, half were recruited here
and half were at the University of Arizona.
And we wanted to see if we could produce weight loss.
And we hypothesized that this 5% weight loss
might improve asthma control.
Now, we did an online weight loss,
patients were meeting online once a week.
We did it at Arizona and UVM,
and you know Arizona don't go to daylight savings time,
and so, we had all the groups got completely messed up.
There are all these things
that you don't think about with mice
that become really important when you do human studies.
(audience laughing)
But nevertheless we managed to do it.
I will say that this is the hardest study that I ever did
and if Olivia had not been involved with this
right from the get-go,
we would still be recruiting patients right now.
Lifestyle interventions are really, really hard.
Nevertheless, we did it.
And we actually got 10 out of the 43 patients
to lose 5% of their weight.
Now that doesn't sound like a lot, I know,
but 23% of our people last 5% of their weight,
which is equivalent to the efficacy
of things like Chantix for smoking cessation.
So, if we use drugs for smoking cessation,
they work in about 22, 23% of people.
So this lifestyle intervention is equivalent
to smoking cessation.
Pulmonologists buy into that.
But what we did see is that
those who lost 5% of their weight,
their asthma control improved very significantly.
So their asthma control score improved by three,
which is a clinically and statistically significant amount.
Their quality of life score improved
by a clinically and statistically significant amount.
Their health related quality of life measured by SF-36
and the impact of weight on their quality of life
also improved by a clinically
and statistically significant amount.
And this is probably the only worthwhile thing
that I'm telling all the clinicians today,
and it is worthwhile.
Because I tell my patients this now,
that if you can lose 5% of your body weight,
that should probably help your asthma control.
And that's worthwhile,
because we sit there, we talk to our patients,
I've got many patients who are 300, 400 pounds,
and I say, "If you lose weight it's gonna help your asthma."
And they've tried losing weight,
and they think they've gotta lose 200 pounds
to improve their weight.
But I can tell them no if you can lose 20 pounds,
that's gonna improve your asthma control,
and so, I would say to the clinicians,
that might be the only helpful thing you've learned
from this hour of talk, but it is helpful.
So the other things
that we're working to follow up from this,
we've got a study that we're doing
that's being headed out
at the University of Illinois, Chicago,
where they're looking at improving dietary quality
to see if that improves asthma control.
There's a lot of data to suggest that poor dietary quality,
actually, is associated with increased airway inflammation
and impaired bronchodilator response,
and I'm really excited about that.
There's a lot of stuff, Jane Gil, we have smiling.
There is a lot of stuff all over the place
about these weight loss drugs.
Apparently, people can't get the diabetes drugs,
because everybody is on sort of these weight loss drugs.
There is one study going on in the US now
using a GLP-1 receptor agonist
that's being done out of Vanderbilt.
I got a call with my DCC at Hopkins next week
to talk about whether we're gonna try and do a study
within our network,
but one thing that we have been doing here,
it's sort of, Lisa in our mouse model,
and this is very much led by Carolyn with Robbie and Bella.
There's a startup in Montreal
that works on cannabinoid receptor R1 inverse agonists.
So these are drugs that have a lot of metabolic effects.
The airway are full of cannabinoid receptors.
These drugs were used I think 10, 20 years ago,
but the earlier iterations of these drug
cross the blood-brain barrier
and caused a lot of adverse psychological effects.
The drugs that we are using now
don't cross the blood brain barrier supposedly,
and they've been developing this drug,
for its metabolic effects and for its weight loss effects,
and so, we did a study with them
where we took lean and obese mice
and we've seen some encouraging data
showing that we can really improve airway reactivity,
particularly the elastance in these obese mice.
Bella is busy running all the ELIZAs trying to figure out
what we've done with inflammation.
And I've been having some discussions with the company
about whether or not we can move forward
and do some studies in humans with this.
So watch this space.
So it's 5:20, everybody's getting tired.
So I just wanna just leave you with a summary,
if you completely slept through the last 45 minutes
-and I wouldn't blame you. -(audience laughing)
So obesity is associated with severe poor asthma control.
60% of poorly controlled asthmatics in the US are obese.
They have about a fivefold risk of hospitalization,
compared with lean asthmatics,
so when you see these patients in your clinic,
they have a real disease.
They don't respond as well
to the medications that we use to treat them.
This disease is associated with altered metabolic function.
We don't really understand what that's doing in the airway,
but we do know that they've got an increased tendency
towards this air trapping
and in data I didn't show you,
it's actually more difficult for them
to recruit their airway after bronchoconstriction.
There's this novel form of asthma
and then there's people that are obese,
and their allergic asthma is really much changed
when they develop obesity.
We've been looking at new approaches to treatments,
CPAP, MitoQ, CB1 receptor, inverse agonists,
not the roflumilast,
we're not gonna take that into a follow up trial,
and lifestyle considerations.
The one thing,
I think 5% weight loss may be really helpful
and I'm really looking forward
to completing the studies
that we're doing on dietary quality,
because I think that will be really interesting too.
So I would like to acknowledge,
I think, if it takes a village to raise a child,
it takes a city for me to do my work.
A huge thank you, obviously, NIH and funders
and the American Lung Association.
There are so many people sitting around this room
and who are not in this room
who've given me so much help over the years.
Thank you all.
And I've got a number of collaborators
around the country
without whom there really wouldn't be much data
to show on this slide.
So thank you, and I'd be happy to take any questions.
(audience clapping)