 Well, on to today's webinar again entitled risk factors and impact of product cost. This webinar is being presented by Dr. Imran Satya. Dr. Satya graduated in medicine from the University of Cambridge in 2006. He gained his membership in the Royal College of Physicians and completed his specialist training in general internal medicine and respiratory medicine. In 2017, he was awarded a PhD in the mechanisms of cough, as well as the British Medical Association James Trust Award and the European Respiratory Society Respire 3 Marie Curie postdoctoral fellowship. Dr. Satya is now on faculty at McMaster and the Firestone Institute for respiratory health, working as an assistant professor in respiratory medicine. He helps on patients with asthma refractory chronic cough and complex airway diseases and had a broad research interest in understanding the mechanism and developing treatments for these troublesome conditions. And so now I will pass it on to Dr Satya. Good afternoon, everyone. Thank you very much for invitation and thank you very much for the invite and thank you all for attending. So my name is Dr. Imran Satya. And I'm a respiratory physician based here at McMaster. And I'm going to talk to you today about risk factors and impact associated with chronic cough. I'm interested in chronic cough is because chronic cough is one of the most common symptom that patients present to their family physician, but also one of the commonest reasons for referral to a specialist in the hospital. And we really don't know much about this condition so I thought I spent some of my time studying this condition and trying to develop a better understanding. I hope you can all see my screen. These are my disclosures. So the main three parts of this talk that I want to talk about is firstly to give you all a bit of a primer on chronic cough. So from a clinical perspective what it is what why does it happen how does it affect people. And how do we investigate and currently treat. So hopefully maybe 1015 minutes on that, then talk about some of the risk factors, and then something about the outcomes of chronic cough from a population based study. So chronic cough firstly is not a new disease. I was able to find this is almost 200 years ago by René Leneck. So he has a famous he's a famous French physician who has a textbook called the treatise on the disease of the chest. And in his textbook, he mentions that, and he used the word Qatar, he used the word acute acute mucus Qatar chronic mucus Qatar, and also dry Qatar. And he says that he prefers the term Qatar to better bronchitis. And what he also said is that chronic dry Qatar or chronic dry cough is most usually an idiopathic affection idiopathic here means that there's no real underlying cause for it that they can identify as individuals who are otherwise in very good health. And interestingly also puts, and this is 200 years ago, that opium repeated in very small doses. I find very efficacious in relieving the symptom. And one of the things that you'll notice is that 200 years later we're still unfortunately doing the same thing in clinical practice. So folks was an Irish physician also talked about chronic cough he describes it as a chronic bronchitis. And he describes it as, in his own words, that when distressing petrol symptoms exist, the morbid physical signs absent, or if present, yet revealing an amount of disease to account for the symptoms meaning that that either the symptoms of chronic cough is disproportionate to, you know, on any underlying disease, or there is no underlying disease. And he says we may make the diagnosis of sympathetic irritation so he 200 years ago realized that there is potentially a neuronal involvement, and he developed this five step approach to investigating and treating this condition where he says that often this is often cough. It's often in the absence of pulmonary disease such as infection like TB and emphysema, always out of proportion. There's the absence of any laryngitis or organic disease. And often when you look into the pharynx it looks absolutely fine. And importantly, they've treated for chest diseases but unfortunately failed to improve their coughing. So this is 200 years ago. Just to bring you back to the modern day I just want to give you two recent cases to give you a flavor of the types of patients that I see. And I often see people who are what I call unexplained chronic cough which is about 40%. So there I investigate them and I can't find an underlying disease to treat or it's refractory where there is an underlying disease but despite treatment of the underlying disease they still coughing a lot. So this is a 59 year old lecturer was a two year history of daily cough, mainly a dry irritating sensation her throat, which is easily triggered by strong smells perfumes and talking. And her cough is so severe that it can cause chest pain and urinary incontinence. And because the cough once it starts she can't stop. She's had to either cancel or stop lectures completely. The cough is so bad that her husband has to sleep in a different room, and she's tried all of the treatments but unfortunately none of them have improved and frustrated because, you know, she's worried and frustrated and causing significant anxiety, because it's you know it's impacting her quality of life and activities of daily living. And as I've mentioned all the investigations are normal. On the other side we have somebody who's a 65 year old male was a retired accountant who's had worsening cough over the last five years with occasional we's after severe bouts of coughing. He describes it as dry, but sometimes the feeling of something stuck in the throat with a severe persistent urge to cough. It's often triggered by changes in temperature lying down or after meals particularly biscuits and toast and cereal dry foods. And he's recently put on some weight and the family physician has tried a antacid therapy called a PPI, but that doesn't help. He was as a child diagnosed with allergic asthma, but he's always been well controlled on low doses of inhaled steroids and bronchodilators. And the cough isn't seasonal. And the family physician has tried higher doses of steroids and another medication called a leukotriene receptor antagonist but unfortunately that didn't help. He's a hypertensive so he was on ramipril, which is often one of the drugs that causes chronic cough but the family physician changed this to candy satan, another type of blood pressure pill, and unfortunately the cough is still persistent. He's really concerned because this is affecting his retirement and social life, and occasionally he felt that he was going to lose consciousness because of the severe bouts of coughing. So this is just a flavor of two of the types of patients that I see in my clinic on a regular basis. One of the things that you'll notice is that patients with this condition often have sensations in the throat and the chest, and they're very easily triggered by low levels of chemical, mechanical or thermal stimulation which in otherwise normal people that isn't the case. So what can be classified into acute, subacute and chronic acute is generally lasting one to three weeks and this is most commonly due to viruses, upper respiratory tract infections bronchitis and pneumonia. But then there's a period of six three to eight weeks when the cough can linger post infectious. And then when it's more than eight weeks. So this is the current definition that we use to diagnose chronic cough that the cough has been going on for more than eight weeks. And often these are associated with asthma nasal disease and reflux disease and I'll explain to you why that might be the case in a few slides. So this is a significant problem so this is data from the US going back 2010 showing that for ambulatory care visits cough is the commonest symptom, why people attend to go and see a doctor. And if you look at over the counter medicine sales this is just taken yesterday from this website, which was on the statistical West website that this is in billions of dollars. The cost per year from 2016 and projected for 2027. The gray bars in the USA. The blue bars in Canada, about half a billion US dollars and United Kingdom also similar levels and worryingly that the trend is going up significantly US. So people will say that this is also possibly due to people taking cough syrup for drug abuse and there is an issue about direct dextromethophane being overused in particularly the younger individuals as a as an alternative to getting a high. And this is a significant concern, particularly in the states in Canada it looks like the numbers are relatively stable although there's a bit of a trend going up in recent years. So the other important thing is that often people think that chronic cough is a relatively benign condition and there's nothing major to worry about. So this is just to explain to you how often people cough in a 24 hour period. So we can wear a cough monitor, which will allow us to calculate and measure in a 24 hour period. So these are some common respiratory diseases, asthma, COPD, interstitial lung disease, and these are chronic coughers. And just to compare these are people who have at a viral infection, like RSV or influenza or even COVID. In the Y axis you can see 24 hour cough frequency. And you can see this is a log to the base 10, and you can see that controls so all people who don't have chronic cough or any limb disease on average, they cough about half a cough per hour. So 12 coughs per day on average but there's a bit of variability around that. And as you're getting more and more towards chronic cough, the median cough frequency for chronic cough patients is about 20 coughs per hour. In a day you're looking at 5600 coughs per hour per day, and people have been coughing often for 10 to 11 years on average in my clinic. So you can see how much that could be impacting them. And it's a bit like imagine you have a viral infection you cough 20 times an hour, but imagine having that for your whole life. So that's an important feature that frequency is a major problem. But also people get really troubled by the sensations associated with the coughing. And these are the common sensations that people describe. So they often describe it as an irritation, a tickle and pleasant sensation, or an itch, and they can be predominantly located in the neck and the throat, sometimes in the sternum and chest and very rarely in the abdomen. And as I mentioned, these patients often start coughing to very low levels of mechanical, chemical and thermal stimulation. And when I asked them in clinic, they can get triggered to their coughing by things like smoke, dry perfumes, smells, cold air, talking, laughing, singing, during meals or after meals and also things like lying down and stress can can make the coughing worse. So these are some of the triggers and sensations that people with chronic cough describe. And because they have such high cough frequencies five 600 times a day, and because they have such strong sensations, and it's impacting their daily activities of living quality of life, it can have significant impact on physical, psychological and social well being. So physically it can cause urinary incontinence, it can cause syncope, sleep disturbance, exhaustion, chest pain and vomiting. Socially it can be lead to absenteeism, it can affect their, their spousal and family relationships, social gatherings, medical consultations, treatment expense and particularly now with COVID. Most of my patients are scared to go out in public because as soon as they start coughing, people think they're infective and want to keep their distance away from them, particularly in public transport and shopping centers. And psychologically it can be very frustrating, embarrassing, they get depression, anxiety and often feel very angry because this is problem has not been adequately addressed. This is some new data looking at what impact cough has on their work ability. So if you look here on the x-axis on this left hand side you have people who are poor, moderate, good and excellent work ability. And here it's divided into no chronic cough, non-productive and productive and you can see that in the poor workability score. There's almost a 15% of people have productive cough and about 5% to 6% with poor and in the excellent group, you, the people who have a non-productive cough or a non-productive cough they have are less likely or the percentage of people in that group is far less. Likewise, people with productive and non-productive cough are more likely to take time off work with sick leave. And in the multivariate analysis adjusting for age, sex, smoking, this group did a calculated sick leave, the odds of taking sick leave based on individuals and females and whether you have productive or non-productive cough and you can see here that the risk is about 50% greater and the ability to have excellent work ability is approximately 30 to 40% lower as well. So this clearly demonstrates that it's having a significant impact on their work as well. So in some of the US data, one of the things that you'll notice here is that people have been coughing for many, many years and I just want to highlight that the average duration of chronic cough is similar to my clinic it's about seven to eight years. In the US it's in females it was nine years and in males it was 7.7 years. Unfortunately, they've seen multiple specialists have had a number of blood tests and some of them have been hospitalized and often taken steroids as well. And if you look at some of the other cough suppressions that they've taken, unfortunately 60% are still taking narcotics including codeine. But as I mentioned, over 200 years since Rene Lanek described using opium and narcotics, you know, much hasn't unfortunately changed, and hopefully in the next couple of years we'll be developing new treatments for chronic cough which are non-narcotics. But unfortunately at the moment we're still using low dose narcotics as one treatment option. So what do you need to know about the some of the basic neurophysiology of chronic cough. I'll spend five or 10 minutes on this. Firstly, it's important you understand that cough is both voluntary and involuntary. Because each of all of us can voluntarily cough whenever we want to, but it can also happen involuntary as a reflex. So talking about the reflex. This is the basic wiring diagram that I show my residents and students. The brain, the airways, and these lines here demonstrate the afferent vagus nerve. So the vagus nerve has two types. One is the C fibers which are chemically sensitive. And the other one is the A delta fibers which is mechanically sensitive. And when something irritates that and stimulates that nerve ending, action potentials are generated and propagate to the nucleus tractor solitarius in the brain. And then the second neuron goes to the thalamus and the third neuron goes to the primary somatosensory cortex. And every single one of us at some point in our life has experienced this as a throat irritation. And often if this is great enough it can cause an urge to cough. And finally, if that stimulus is great enough, it will it was coughing. And in chronic cough, there's a problem with this wiring in that this pathway has become hypersensitive or hyporesponsive, and we're not completely sure which part it is that is the problem but we think it could be a combination as well. And because of this, we often consider conditions like asthma where you have a lot of mucus inflammation, particularly eosinophilic, or even neutrophilic. These are all capable of sensitizing these airway nerves. But you also have to remember that the vagus nerve has afferents which send signals from the esophagus. So things like acidity can also sensitize these nerve endings. And also the nose has a trigeminal nerve, which also goes back vagus nerve in the in the brainstem, and therefore anything which is wrong with your nose particularly eosinophilic inflammation or allergic rhinitis. This condition can also sensitize these airway nerves and make you want to cough. So this is one of the reasons why we often try to understand and treat for asthma, reflux disease and nasal disease to try and control the coughing. And therefore, cough can be because of increased emulation. It can be because of acidity and because of inflammation of the nose, but also maybe that the nerve itself is also hyper excitable. And also, recently there's evidence to suggest that the brain itself has evidence of central sensitization, or something slightly different called impaired inhibitory controls this idea that the inhibitory pathways which are tonically active, have stopped working and therefore signals which otherwise wouldn't make you cough are now making you cough. So things like mucus, eosinophilic, bronchial, constriction, reflux, environmental, occupational disease is now becoming very important as I'll come to in a second. And in terms of central treatments, we often give people, as I mentioned morphine, but also some studies showing evidence for pregabalin, gabapentin, and amitriptyline, and also now speech therapy as a treatment option for cough suppression as well. So that's a bit of a background and just one slide on some nerve channels found on C fibers. As I've mentioned before, the nerve endings of C fibers are chemically sensitive and they, they express these trip channels called trip V1, which is sensitive to chili pepper extracts and really spicy food. It activates trip V1 on your taste buds, and that that's what gives you the heat sensation. So it's responsive to chili pepper extract but also we have trip A1 which is sensitive to acraline and smoke, but also aldehydes and perfumes and aerosols and now you can kind of get to see why patients often start coughing to exposure to these at low levels. Because these are also temperature sensitive and maybe that's the reason why people respond to cough by changes in temperature, particularly hot and cold air. And also this ATP which we'll come to, which has become a new area of interest because now we have drug therapy which is blocking P2X3, which is causing significant reduction in chronic cough which is great news. And we also have things like inflammation like prostaglandins and bradykinins, which also bind to these receptors making you want to cough. The adelta fibers are also acid sensing ion channels so they respond to things like hydrogen ions and acidity from reflux, but also we have mechanosensors which are sensitive to things like mucus. So these are all potential triggers to coughing and it works via very precise ion channels and therefore treating these potentially with newer ion channel antagonists might be a treatment option. So what do we do for patients in clinic? So we recently wrote a guideline and in that guideline these were the four fundamental principles. We want to investigate patients to rule out serious underlying lung disease or heart disease to diagnose to prevent over and under diagnosis, treat based on specific disease and traits, and also then monitor to ensure effectiveness and reduce side effects and titrate treatment. So this is a stepwise approach. This is published recently in the Canadian Journal of respiratory critical care and sleep medicine. And in step one in primary care we're advising and recommending to check, test and refer. So check the cough history, check if they're on ACE inhibitor, stop smoking, do a basic spirometry with reversibility, a chest x-ray and a CBC. And if there's signs and symptoms of coughing or blood, weight loss, fevers, or abnormal chest x-ray, then they should be referred urgently and hopefully be seen within two weeks. And depending on your first investigations and clinical acumen, if you think they have asthma, COPD, chronic rhinocinositis or reflux disease, then they should be treated according to those pathways. If there's smoking to stop smoking, and as I've mentioned before, if there's an ACE inhibitor then they should be switched. If however the cough persists, then in secondary care my job is to confirm and check the diagnoses of asthma, eosinophilic bronchitis, reflux disease, esophageal dismutility, rhinocinositis, and inducible laryngeal obstruction and muscle tension dysphonia. And these are some of the tests that we can do. I also do some basic cough severity scores using either a 0 to 10 numerical scale or just a visual analog scale. And there are some quality of life tools that we can also do. And then I only treat based on finding an underlying disease. If after treating that or not finding anything, then we are in the position where we can say, well, is this cough truly refractory to these conditions, or is it completely unexplained. So now my options are either to do some speech therapy and cough control therapies. This includes education cough suppression exercises, cough avoidance strategies, and reducing laryngeal irritation and some counseling. Or the other option which you can do either alone and in combination is to give people centrally acting neural modulators, such as pregabalin, gabapentin, low dose morphine for a two week trial, and amy tryptoline. Evidence for this isn't great. There are small studies. Many of them are have unvalidated endpoints. But these are the best that we currently have from the guidelines. And then based on these trials of treatment, we then assess benefit usually on our second clinic follow up. And if there is benefit we monitor side effects, particularly for some of these drugs because they can cause nausea sedation drowsiness and unsteadiness. So we try to get them down to the lowest dose possible to help. If they don't help at all, then we try something else, or we recruit them into clinical trial. So this is the kind of overall pathway that we use in our clinical practice. So I think I'm halfway through. And the last 20 minutes, I hopefully want to just go through some of the epidemiology of chronic cough that you might be interested in as well. About six or seven years ago, one of my colleagues did a systematic review and meta analysis of the prevalence of chronic cough globally. And what they demonstrated what was on average, the prevalence across the whole world is almost 10%. What I notice is that there are some countries which are really red, like Australia, where the prevalence is 18% in Europe is 13% in America is about 11%. And in other countries like Asia and Africa where you might suspect chronic cough to be more of a problem, particularly with HIV, TB, AIDS, and pollution in China and these kind of, you know, it's really quite low. But we don't understand why it's so variable and various, you know, people have speculated it could be because the definition that they've used is the old chronic bronchitis definition, which has been around for a long time, since 1950s and 60s, which Charles Fletcher developed, which is chronic cough which is productive of sputum and most days for at least three months in a year for two consecutive years. So the explanation is that, you know, they've used the wrong definition. The other explanation is that, okay, maybe that we just don't have enough studies from those countries. But then more recently, when they've looked at studies which have used the definition, and you'll still see that within the European continent. In UK, 7% in Finland, Germany 5%, Copenhagen in 4%, and even in South Korea, Japan and Nigeria, you're looking at one to two, 3%. So it's even with the eight week definition, there's still high variability, and even within the European continent, which is very closely associated obviously, especially in location wise that there's still a significant variability. So this has been going on and some uncertainty of why such variability exists. So we wanted to, and at the time I noticed seven years ago, we had no data on Canada, because there was no data collected. So when I came to Canada in 2018, I went to speak to Parminda, and I said, look, I'd like to study chronic cough in the CLSA, and he, we put a proposal through, and we studied chronic cough. I did want to point out here that this is, as you know, for patients recruited from the age of 45 onwards, so it's not 18 plus, it's 45 onwards. And the question that was asked in the CLSA was, do you have a daily cough every day for the last 12 months? So it's a 12 month, not the eight week definition. But at least it includes everybody, by definition, who's more than eight weeks. So based on this, the prevalence in the CLSA of the 30,000 participants at baseline was 16%. So I was quite surprised by this because this is like the second highest in the world after Australia. But a lot of these coughs obviously, as you can see driven by people who are current smokers, but even if you look at non smokers, you're still, you know, around 10%. It's still quite high, even in non smokers. And you'll notice that increases with aging. And one important thing here which I want to point out is that it seemed to be slightly more common in males and females, which is slightly different to what we see in clinic. The other important thing we noticed was that prevalence was lowest in Quebec, around 10% and highest in Ontario around 16%. And the incidence because we have longitudinal data from follow up one was also lowest in Quebec at 8% and highest in Ontario at 12%. So at for the baseline chronic cough, we also looked at variables which may increase or reduce the risk of chronic cough and you can see here that having lower airflow or worse airflow obstruction. Lower FEV one, the presence of other symptoms, and particularly asthma and COPD significantly increases the prevalence of chronic cough at baseline. But I don't think that's the interesting thing for me the interesting thing is that if you have no airflow obstruction, normal lung function, no other symptoms, no asthma, no COPD, the prevalence is still 11 to 12%, still very high. And likewise, the incidence pattern is very similar. We don't have any other incidents globally to compare with the only study that I'm aware of is a Rotterdam study, which looked at the incidence of chronic cough in Rotterdam. And that was around 1.5 per 100 person years. So, you know, this is almost three times higher, which is quite high. So it's important to understand that the chronic cough question is a dichotomous variable. It doesn't ask about frequency. We don't ask about severity, and we don't really significantly have any cough specific quality of life questionnaires. So that's an important limitation. It's important to understand that it's self reported. It's an older population above 40 or 45. And it's from the general community and these are not people recruited from specialist centers. It's predominantly white and from an urban population because from the data collection site they had to be within 25 to 50 kilometers. And my biggest question here is, if the prevalence is really one in 10 in the general community, you know, I would have expected more people in clinic. You know, all of us know people, but you know, maybe people with chronic cough, they're trying to suppress their cough. So this one in 10 or 10% chronic cough in the general community still. I'm not sure whether this is an overestimate, but it's, you know, I'm still trying to fully understand this and be critical of my own data. So because of the issues related to Quebec and Ontario and the differences, we stratified the analysis based on whether you're English speaking or French speaking and I will point out here is that we did this based on which language, the participant completed the in French, so that was their predominant or dominant language and likewise for English. So if you look at the English speaking participants, no surprises that cough increases with age. I've mentioned before that it's more common in males and slightly greater risk for developing chronic coughing males in smokers in being overweight and obese. But when you look at the location issues, if you're English speaking, living in Ontario, compared to somebody who's living in Quebec, it's almost 41% lower risk. And then Nova Scotia 33% and 20% newfoundland. So as you're moving east, something is going on here, and also out in the west and tension north. It's numerically lower but not statistically significant, except for in British Columbia it's about 13% lower, but Ontario seems to be the highest. So it suggests that location, even if you're English speaking seems to be an important risk modifier. But if you're French speaking, and you compare with French speaking in Ontario versus French speaking Quebec, it doesn't really make a difference. And as you know, many of you know, we'll know that most of the people who had the question I done in French were either living in Ontario or Quebec, we don't have anything from the other provinces. So it suggests that both language and location both matter. And I don't fully understand why people have suggested it could be because of climate could be because of pollution. It could also be because of their social understanding because when somebody's reading the question that do you have a chronic cough every day for the last 12 months. Some people might interpret that as do I have a troublesome cough. Do I have a cough which is troubling enough for me to go see a doctor. So, you know, some people think it's only a cough, you know, it's fine. It's not a major issue. Maybe that some people, you know, don't, you know, have under reported the maybe a response bias. So I don't fully understand in all honesty the differences but this is something which we're looking into now further as well. So one of the things that I wanted to explain was in the population level, we're seeing more males and females saying they have chronic cough. But when you look at the clinic, this is what I see. And this has been replicated in most European and US clinics in that it peaks in the 50s and 60s, and it's almost twice as more common in females and males. And this is what we also see also in the clinical trials. So although we're seeing male predominance in the population, we actually seeing female predominance in the clinics. And that could be because is that people with chronic cough it's affecting the females more they have higher frequencies and higher severities and there is some data to support that. That could be one explanation. The other explanation could be that for men it's not as bothersome so they don't go see a doctor and they can't, you know, they're a bit more stoic about it. That's the other possibility. So if you look at in China, you'll notice that the peak here is around 30 to 40 compared to 50s and 60s in Western countries. And again, you'll notice in China though, and this is in cough clinics, it's more male dominant, not female dominant. Chinese colleagues and collaborators have mentioned that it's there's some social stigma associated with coughing, particularly in females, and often, you know, it's not seen as a nice thing. So there's a lot of less people that they're seeing in clinic who are female, possibly because of that. So if you divide that by underlying disease, like cough variant asthma is significant bronchitis reflux, a topic cough, you know, it doesn't seem to be female predominant in China in Korea. Also, we're seeing chronic cough is more common in males. When you do a multivariate analysis in chronic cough. Again, female sex doesn't seem to have a significant association with developing chronic cough. So, in the far east we're not seeing the same patterns. And I just wanted to point that out. So in this going back to the CLSA we've looked at what are the other associated comorbidities which might impact the incidence. So this is age, sex and smoking adjusted. And you'll notice here that there are a number of cardiovascular conditions like heart attacks hypertension, congestive heart failure and pneumonia and influenza which you might expect to increase your risk on developing chronic cough. I will point out here that in these conditions all of these conditions people would have been prescribed an ACE inhibitor. And at the time when we were doing this analysis almost three years ago to three years ago, we didn't have the ACE inhibitor data available. So, so we don't know whether or not this is being driven by being on perinferno ramipro. But interestingly, we also noticed that some, some other conditions like pain mood disorders, anxiety and depression are just as important in developing chronic cough and as I mentioned you that wiring diagram. One of the things that we really noticing in the mechanistic studies is that these mental health disorders pain mood anxiety are really impacting those neurons in making people cough. So we wanted to look into this into more detail because we see people in chronic cough clinic who are anxious and depressed, but we don't know whether this is cause or an effect. So we looked at this in a multivariate analysis where looked at the risk of developing chronic cough, based on having higher depressive symptoms scores based on the high CES D10 or the psychological distress K10 more than 22. But we also added in personality traits as in the very in the multivariate analysis. And what you'll notice here that having psychological distress and depressive symptoms at baseline when you have no chronic cough these are baseline scores increases your risk of developing chronic cough by about 20 to 22%. And that's independent of age, sex, smoking, asthma, COPD, all the other bad stuff. And likewise for personality traits, there doesn't seem to be any statistical significance, although one can argue that having low conscientious scores. There's a bit of a trend to it being almost significant in leading to chronic cough three years down the road. One of the other interesting things that we know is that, what about chronic cough, how does that affect anxiety and depression. So here we turn the model around, and we put in chronic cough at baseline incident and persistent in the as an exposure, and we adjusted for psychological distress and personality traits, and whether or not they had higher incidents of depressive symptoms three years later. And you can see here clearly that again, chronic cough also causes or leads to higher depressive symptoms, and the same pattern. We see also for psychological distress that chronic cough increases your risk of higher symptoms of psychological distress so what it kind of suggests is that there's a bit of a three way relationship that depressive distress and chronic cough, incident chronic cough, they're all interrelated. And some of these personality traits don't directly impact chronic cough but may do so via impacting depressive symptoms and psychological distress. And this kind of relationship has also been demonstrated with chronic pain now in the in the Copenhagen study, where people have noticed that increasing frequency of pain from non to daily. Increase prevalence of chronic cough in the Copenhagen study. And in their multivariate analysis what they noticed was that having chronic car pain on a daily basis increases your odds of developing chronic cough. And likewise, having chronic, sorry, having chronic pain also increases your risk of developing chronic cough so it's again interrelated condition where pain can increase your risk of chronic cough, and the other way around as well. Finally, I just want to touch on mortality because we don't have much data on how chronic cough impacts mortality. We know that from the last 200 years people who have productive chronic cough with chronic bronchitis they're associated with deaths due to TB, pneumonia, COPD. But this is a multivariate model where we've adjusted for age sex smoking BMI and respiratory diseases, and independent of all these things, productive cough increases your risk by about 50%. But importantly, dry chronic cough doesn't which is which is somewhat reassuring. And this is currently under second round review and should be hopefully published in the next couple of months but this is new data which we just become available. So I want to end there and need some time for discussion, but just to summarize that chronic cough is a cough which is going on for more than eight weeks it can be refractory to underlying disease or can be unexplained. We think it happens because of activation of neuronal pathways in the peripheral and central nervous system. It reduces quality of life increases mortality, particularly with productive chronic cough, and we currently treat people by excluding serious causes and then reducing the cough with centrally acting neuromodulators. We can see that there are risk factors such as age sex smoking, respiratory cardiac disease but now also anxiety and depression all impact at the development of chronic cough and often, as I've mentioned shown they can be often interrelated. There seems to be a suggestion that the language location and culture matters in developing chronic cough, and that there are important differences from what we see in the general community in epidemiological studies, and what we see in specialty clinics. From population level it's important to mention that chronic cough increases mental health disorders and chronic pain. It reduces your ability to work and increases sleep, but also increases mortality with productive chronic cough but not dry chronic cough so I'm going to end there. I would like to make out a big shout out to Alexander, Mehio, Alex and Sohail and Parminda who have really been helping me to analyze and get this data published and hopefully you'll see some more data related to hopefully with social participation activities of daily living which we're currently working on, and then also looking at pollution and climate differences as well. And these are my collaborators in Canada, in Manchester and also my funding bodies. So thank you all very much for joining in. I think I've left exactly 15 minutes for any questions. I noticed that there's some in the chat. If there is anything I'm happy to answer. Yes, well thank you very much. I don't see any questions in the chat quite yet but sometimes they sometimes we do sometimes we don't. Great presentation I know I learned a lot. I'm going to start with one question that well I'll post to and we'll see where they go. But one thing that I was, you know, oftentimes to think about next steps but obviously there's lots of opportunity to explore the social environment around that you've uncovered, as well as the different neural pathways, the links to mental health. I'm just wondering if you can talk a little bit about your, your sort of next steps in terms of exploring those things either with or without the data. And then the other thing I thought about is, you know, COVID right. This is probably the first presentation I've heard in quite a while that hasn't somehow talked about COVID. But I imagine that there's, there's a lot you need to tease out in terms of chronic cough as a lingering factor in COVID so just two things maybe you can touch on and then we'll see if any more questions. I'll talk about the second question first. So, at the time when we started doing this analysis, it was actually pre COVID before February March 2020. So, at the time, we, we didn't have much COVID data. I think the CLSA now has COVID specific data and post COVID data so that will be interesting to look at. From a clinical perspective. I think I'm seeing a lot more post COVID chronic coughers. And some of the published data suggests it can be as high as 20% of people who have had COVID develop a chronic cough. And what's really interesting is that people in the clinic are saying that when I had the COVID. I actually didn't cough. I just got fatigue, malaise, fever, sore throat. I didn't cough at all. And then the cough only started a week or two afterwards. And then it kind of never went away. And so that's an interesting kind of phenomena which I'm trying to understand that what is the neuronal mechanism behind that has the virus sensitized these airway nerves and that's taken a bit of time for neuroplasticity to kick in. And then that's left them with this terrible cough which then doesn't go away. So that's that's some of my own clinical feelings. With regards to the other question the first questions about the mental health disorders, and particularly with depressive symptoms and psychological distress. Which we need to look into more carefully is the medication data, because it's available, but at the time of doing the analysis we didn't have it all cleaned up. But it will be interesting to look at that does, if you have psychological distress and depressive symptoms, and then you were treated for that baseline. But one, does your cough go away. And the reason why I say that is because one of the treatments that we use in clinical practice, sometimes are is amitriptyline to reduce coughing and amitriptyline is a antidepressant. And one of the things that I'm trying to understand is trying to relate to what we see on an individual patient in clinic to see whether or not that signal can actually be detected and found at a population level. And can we work in both ways so I do, you know I see patients in clinic I do mechanistic studies with basic science I do a bit of epidemiology now, and I run clinical trials. And what I'm trying to understand is, how does. How can we understand what we see at the population level and experiment and individual level, and how can we see, you know, observe what we're seeing in an individual level in clinic and then scale it up a population level. So the antidepressant story is an interesting one because I'd really like to understand that more carefully. More detail. And so that's something which we've been thinking about as well. So there's going to be no shortage of work to dig ourselves into. Great. We just had a request if you can put up, and there might be a follow up question once you do the slide on side effects. Or risk factors, I think I don't know the side effects or risk factors there's two different requests might be one in the same and then while you put that up. A participant asked and you can use your discretion how you answer this one, but my sister has had a chronic cough. Yeah, I saw that. You know, would drug therapy be useful after all this time. Yeah, so as I mentioned, you know, on a I have a cough clinic specifically for chronic cough every Tuesday afternoon at McMaster and Friday mornings at St. Joe's, the Firestone, and I routinely see people who have been coughing for 1520 30 years. I also see some people coughing for five years but on average, the median or median is about eight to 10 years. So sure, you know, it sounds like your system probably needs to come to my clinic to get assessed and treated. So that's the first thing. With regards to side effects. So there's some, this is I think this is the side effects of the treatments that we currently give the slide. So when we've excluded and ruled out everything else and we really think that this is going to require some centrally acting neural modulators. So one of these options pregabalin gabapentin, which as you know, or might know is anti epileptics, but there's two randomized control trials for each showing that these may be effective. And the kind of side effects that people get are things like unsteadiness. Sometimes they can get dizziness. Sometimes you can get a bit of weight loss or weight, or even hair loss I've seen with pregabalin. But one of the things that I do is we, we give people very, very low doses. So the typical dose of pregabalin for epilepsy is 150 milligrams twice a day. And for gabapentin, it's can be as high as 603 times a day. But I stop people often 25 or 50 milligrams twice a day for pregabalin, and then slowly increase to maybe 100 twice a day. And I start off at 103 times a day and maybe go up to 303 times a day and nothing more than that. For morphine, I actually morphine is usually my first, first line therapy and it can be quite scary when I say to people, oh, I want to give you an opioid for chronic cough. But in my experience out of the four that I've listed that it has probably has the best evidence, and I have the best experience with that. It's just five milligrams twice a day, which is a very, very low dose. And at that dose, you know, the only side effect that people complain of usually is constipation. And we, that can be easily treated with laxatives or fruit and veg and just water. And I only give people a two week trial, just to see how they're going. And if after two weeks it doesn't work, then you stop it, because the evidence suggests that the effect is very, very quick. So, so people often try that. Some people who don't want to take morphine sometimes try codeine or tramadol, but the evidence for that just doesn't exist. But some people do try that off label use as well. So, so those are the kind of side effects that we have to monitor and observe for. I have a question here about chronic coughing lung cancer. So, yes, there's a one of my colleagues Emily Harley published a paper on coughing lung cancer. And the frequencies actually quite similar, it can range from about 15 coughs per hour to 20 coughs per hour so it's still quite high for frequency. The interesting study is that there's actually a randomized control trial looking at a prepitant, which is an anti nausea drug. And there's evidence suggests that that a prepitant reduces cough frequency as well. And the mechanism behind that is a prepitant is a neurokinin one antagonist. And these neurokinins one receptors are found in the brainstem. If you block this receptor, you reduce nausea, but also improves coughing. So there's a paper one paper that I'm aware of looking at coughing lung cancer which has improved cough frequency in lung cancer. But it's very expensive a prepitant, but maybe other other drugs will be coming out soon. Can you actually the slide that the Adeline had wanted was the one just before the end. This one. This one. I'm not sure. I think it might be this one actually. So she may have a specific question. And there was a question that wasn't posted in the Q&A Q&A but I will answer it or ask it. Sorry if I missed this, but does chronic cough on its own lead to physical damage, perhaps in the respiratory tract. So what we do see is that it doesn't cause damage in the lungs itself per se. So having chronic cough doesn't impact you, your lung function or getting fibrosis or getting cancer. What we can say is that it causes a lot of chest pains, rib fractures, intercostal muscle tears, diaphragm pain, stomach pains. So it doesn't cause damage inside your lungs per se, but it can affect the chest wall a lot. And that in itself can be physical damage. A lot of women, 50% of women in my clinic who have chronic cough have urinary incontinence. And the patient was fecal incontinence. And they walk around with pads. So you can see that it depends how you define physical damage, but you know, as I've explained, you know, it's, it can cause significant problems. Some people have terrible headaches because of lots of coughing. Some people lose consciousness, particularly men, they get syncope or presyncope and feel as if they're going to lose consciousness. But you've got to be very careful when you're driving. And if you go into a battle chronic cough, often patients, they start coughing and then they can't stop coughing. And that can be a big problem as well. Great. Well, I don't see any more questions and that's actually good timing. And thank you very much, Dr. Santa for your presentation and thanks for everybody's participation and questions. I'd like to remind everyone that the next deadline for our data access application is January 18th of 2023. You can visit our website under data access to review what data is available as well as additional details about the application process. I'd also like to remind everyone to complete your anonymous survey when you exit the Zoom session today. The next day let's say webinar is entitled examining the bidirectional association between adiposity and cognitive function among middle-aged and older adults in the state. It will be presented December 14th at noon by Dr. Mohammed Nazma Stakey and Dr. Peter Hall registration details for the webinar will be posted on our website. And also remember the CLSA promotes this webinar series using the hashtag CLSA webinar and we invite you to follow us on Twitter at at CLSA underscore ELCV. Everyone have a wonderful afternoon and thank you again. Bye.