The science of coughing

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

More people seek medical advice for an unwanted, nagging cough than any other ailment. In some people their cough can persist for years without relief, as effective treatments are not readily available.

Stuart Mazzone is Professor in Neuroscience in the Department of Anatomy and Neuroscience, University of Melbourne. Stuart heads the Mazzone Laboratory within the School of Biomedical Sciences, which is internationally recognised for remarkable work in the field of cough and respiratory sensation.

Stuart and his team discovered that separate pathways in the brain are involved in the response to a good cough (needed to clear airways, or to ensure optimal lung health) vs a bad cough (a sign of disease).

Stuart Mazzone sat down for a Zoom chat with Dr Andi Horvath.

ANDI HORVATH
Stuart, you study coughing. We all have experienced the cough reflex when we've sort of eaten something that's gone down the wrong way, tell us more about the cough from a scientist point of view?

STUART MAZZONE
Cough is a very important defensive reflex that we have. We need it in order to clear the respiratory system from things such as the example you gave of food or other substances going down into the respiratory passages that can obstruct breathing. So humans have a very effective cough reflex that we use to clear the respiratory system of these types of inhaled substances, but also, from things that might accumulate within the respiratory tract, for example, in diseases; so mucus and other sorts of secretions.

ANDI HORVATH

So what is the relationship between coughing, our lungs and of course, the brain?

STUART MAZZONE
Andi, we think there is a very important relationship between the respiratory system and the brain. So cough, as I mentioned, is a reflex and reflexes rely on the nervous system. So the lungs are heavily innervated by sensory neurons that detect these stimuli that initiate coughing and those signals are sent into the brain and used to encode the cough respiratory pattern. Now, in addition to that, some of the information also enters the higher brain, places of the nervous system where sensations are encoded. So during a coughing event, you'll also notice the feeling of an itchy or an irritated airways and that's because those signals are being turned into a sensory experience in addition to the cough mode of pattern that defines a cough.



ANDI HORVATH

Coughing these days is often a sign of COVID, but COVID aside, is coughing also a disease state in some situations?

STUART MAZZONE

Cough is very interesting, Andi, because it accompanies more than 100 different conditions of the respiratory tract. It can also accompany diseases that have nothing to do with respiration, for example, people with reflux disease where gastric contents into the oesophagus often have chronic cough. It can also occur in people with no known underlying disease mechanism; a condition we refer to as being idiopathic chronic cough. For that reason, more and more now, we are beginning to think of cough as being its own disease and in fact, the disease as it's termed now is referred to as cough hypersensitivity syndrome where people who have a chronic cough not only cough too much, but they cough to inappropriate stimuli.

ANDI HORVATH
There is a cultural component to coughing as well, it's when we kind of want to underline or put in inverted commas something we've said or don't want to say.

STUART MAZZONE
I suppose what you're suggesting, Andi is that cough is not just a reflex, that in fact we can voluntarily cough and you're absolutely correct in that sometimes we use that in everyday communication. But in addition to being able to voluntarily cough, we also have some capacity to voluntarily suppress our coughing and you see, both of these scenarios play out in everyday life. So individuals for example during a concert or a movie may often try to stifle their coughing in order not to disrupt the audience around them. As you've mentioned, in those same circumstances when one or two people initiate a cough, often other people join in.



ANDI HORVATH

So there is such a thing as cough contagion?

STUART MAZZONE
Absolutely. In fact, there's a number of studies that have looked at this; if an individual within an audience begins coughing, it's more likely that other individuals around them will also join in coughing as well. So cough can be contagious and it's not through an infectious agent, but it's rather driven by voluntary behaviours that involve the brain.

ANDI HORVATH
Actually, that makes sense because, during a concert, there's sometimes a glut of coughs. It's sort of like someone's coughed, so you feel like it's okay to cough to clear your throat if the air is a bit dry. I want to talk about the disease state, the chronic cough because that's what you set out to explore and I'm keen to know why did you head in that research direction?

STUART MAZZONE
Chronic cough is a very prevalent condition, Andi. Around about 10 percent of the population globally experience chronic cough which is defined as having a cough that lasts longer than eight weeks in the absence of the respiratory tract infection. So it really is a very significant burden on the healthcare system, it's a significant burden for individuals who have it. Their cough can last for decades and some of these individuals cough more than 200 times every hour of their waking lives. The problem is that we don't have any decent medicines to treat people with chronic cough. Current over-the-counter drugs offer little benefit over placebos and other drugs such as opiates which have been used in the past to help treat patients with chronic cough are of course used less and less these days because of their addictive nature and the other problems associated with opiate use.

So for that reason, there is a major gap in the healthcare market for effective antitussive agents that can be used to help control chronic cough in patients who have this debilitating condition. Now, our interest is in understanding how the nervous system becomes dysfunctional in these patients because we think and we believe that if we can understand the problems that lead to chronic cough, then we have a better chance of designing drugs to target those problems to relieve this condition.



ANDI HORVATH
Stuart, tell us how did you approach this? How did you experiment on coughs? Do use humans or guinea pigs or rats?

STUART MAZZONE

We use all of the above. So my laboratory has a long track record; we've been doing this for almost 20 years now trying to understand these neural networks or these nerve circuits that are important for controlling coughing and we use a variety of approaches to do that. A number of years ago, we made an interesting discovery; we were playing around working with this form of herpesvirus trying to turn it into a tool that we could use to map nerve circuits and what we discovered was that in fact, there was a new previously unidentified nerve circuits in the brain that was involved in coding sensations from the respiratory system. This led us down the path of trying to understand what this nerve circuit in the brain was involved in.

More recently, what we've been doing is using humans and guinea pigs to ask the question of whether this new nerve circuit is important for cough and I'm excited to say that our most recent research indeed argues that we've discovered an entirely new brain circuit for controlling unwanted coughing in patients with disease.

ANDI HORVATH
Wow, does that make it then a target for drugs that can suppress those nerves in the chronic cough?

STUART MAZZONE
We hope so. As I mentioned, cough is also a very important protective reflex that we have for clearing the airway of aspiration and other secretions. What we think we've discovered is that there are in fact two cough pathways in the brain; one of those pathways is critical and essential for controlling that protective cough that we need, that if we block that protective cough, we end up with aspiration pneumonia and ultimately, with death. The other pathway we think is the one that's involved in cough and disease, so if we are correct about our discovery, then, in fact, we may have an opportunity to target unwanted cough without impacting the very important protective cough that we need for survival.

ANDI HORVATH
So we can keep the good cough, but get rid of the bad cough?

STUART MAZZONE
That's our hope, Andi, absolutely.

ANDI HORVATH

Can I just ask, what does a coughing guinea pig sound like?

STUART MAZZONE
[Coughs] They sound very cute, Andi. They have a very high-pitched cough. It is audible. Unlike humans, they don’t put their hand over their mouth, so they're a little bit naughty, but it is quite a sight to see.

ANDI HORVATH

What about the rat, does that have a cute cough too?

STUART MAZZONE
The rat doesn't cough interestingly enough, so rats and mice don't have a cough reflex. They use other types of respiratory manoeuvres to clear their airways and so that's one of the reasons that we use guinea pigs in our cough research.

ANDI HORVATH
I see. Can you just do one more guinea pig cough for me? That's the best thing I've heard all day.

STUART MAZZONE

[Coughs]

ANDI HORVATH
That is almost cartoon-like. I can imagine some sort of southern belle doing that cough [laughs]. Now, I want to ask you about coughing… coughing can sometimes save lives. When do we need to cough?

STUART MAZZONE
We need to cough to clear the airways, so some cough is productive cough and that in a sense is good cough. So for example, during excessive secretions, coughing becomes very important. People with cystic fibrosis, for example, need to have an effective cough in place in order to clear those excessive secretions from their airways and in fact, one of the cruel ironies is that patients with cystic fibrosis often have a down-regulated or a blunted cough reflex and so lots of manoeuvres are used clinically to help improve cough in those sorts of patients. We also need it in everyday life; during eating dinner, you may have experienced food going down the wrong way as we often say which is actually aspiration of food into the airways which can cause an acute obstruction and lead to very serious problems with airflow and gas exchange and as a consequence, ultimately, it can be fatal.

So there are circumstances where we do require a very effective and intact cough reflex and those types of coughs we think rely on a very different pathway to the cough that is prevalent in disease.



ANDI HORVATH
Stuart, how did you enter this area of scientific research?

STUART MAZZONE
It's an interesting story because it evolved for me over a little period of time. During my PhD, I was always interested in understanding the airway nervous system and how it was involved in airway defensive reflexes. But I wasn't really thinking about cough until I came to know a very famous respiratory physiologist by the name of Professor John Widdicombe. Now, John sadly passed away a number of years ago, but in his later years of life, he and I became quite good friends in fact and one night, I was fortunate enough to have dinner with him and his wife in a little Italian restaurant in London and we were talking about all kinds of things respiratory physiology. John said to me you know, one of the biggest impacts that somebody can have in the field would be to understand what the brain is doing during coughing and that got me thinking because really at that point in time, the brain was a black box in terms of understanding its role in cough. That was the sort of thing that really inspired me to tackle and try and open that black box and shine a light onto the role of the brain and cough.

ANDI HORVATH

Stuart, what sort of things have made you stop and think or have surprised you about your research adventures?

STUART MAZZONE

Yeah, that's a good question, Andi and I think for me, one of the biggest surprises has been the initial slow uptake that my fellow researchers and clinicians had towards considering the brain as being a targetable organ in terms of treating respiratory symptoms like chronic cough. But pleasingly, in more recent years, the great excitement that they've shown towards these discoveries and I think it's an important lesson in science is that even if your ideas and your discoveries aren't taken up immediately, keep pursuing them because if you feel that you're right and if you feel that you're onto something that's important, then the rest of the pack will come along with you eventually.

Now, in my own experiences, there is a very strong international effort to try and understand how we can target the nervous system and the brain to control chronic cough in patients.

ANDI HORVATH

What are some of the misconceptions that people have about your area?

STUART MAZZONE

I think the biggest misconception is that cough is simply a lung problem and we know now that it's not. For example, there are many conditions in which cough can be a presenting symptom that simply don't involve the lungs at all. People for example even with a blocked ear can have a chronic cough interestingly enough. But in saying that, I also think that one of the biggest misconceptions is that cough is simply a reflex and that in defining it that way, that means that there is no level of behavioural control. Now, in fact, we know in many patients with chronic cough, the amount of reflex coughing that they have is quite minimal. Much of the cough is driven by a perception of something irritating their airways; it's a behavioural cough and it's controlling this behavioural cough that's proven to be very, very difficult, but something that we are hopeful that we might be able to start tackling now that we understand the neural elements involved in that behavioural coughing.

ANDI HORVATH
This may be an awkward question during COVID times, but what would you like us to think about next time we see someone coughing?

STUART MAZZONE

It's a fantastic question, Andi because I think it's really important to remember that not all cough is infectious cough. So not everybody who's coughing is because that they have some sort of nasty infection, a viral infection or a bacterial infection. In fact, many people have a chronic cough that's completely unrelated to infection. These individuals may be suffering with a very protracted problem for which they are finding it very difficult to treat and so I think we need to keep in mind that some people - many people in our community, in fact, have a chronic cough and it's not necessarily because they are ill with some nasty bug.

ANDI HORVATH
Professor Stuart Mazzone, thank you.

STUART MAZZONE

Thank you so much.

CHRIS HATZIS
Thank you to Stuart Mazzone, Professor In Neuroscience in the Department of Anatomy and Neuroscience, University of Melbourne. And thanks to Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on November 9, 2020. You’ll find a full transcript on the Pursuit website. Production, audio engineering and editing by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis. Join us again next time for another Eavesdrop on Experts.