All right, I think in the interest of time, we'll go ahead and get started. Thank you all for being present at our session. On my part, which will be the first quarter, is focused on refractory chronic cough. Is it a symptom, or a disease, or both? And hopefully we can answer that in the next 12 to 13 minutes. So my name is Matt Navarri. I am Assistant Professor of Medicine at Loyola University in Chicago. And it's nice to get out of the cold and be in Hawaii right now. So our objectives for today will be really to kind of focus on some definitions for my part of the talk, in which case we'll look at the way that chronic cough is explained or defined, and how refractory chronic cough comes about. And also looking at unexplained chronic cough and potentially the pathophysiology behind this disease entity. So as we all know, we've taken care of these patients, whether we're an internist, family medicine doctor, allergist, pulmonologist. We see these patients. It's estimated that approximately up to 10% of the world population at some point in time suffers from chronic cough. And if you average that out, that's approximately 600 million people. And I'd like you to let that sink in for a second. That's a significant number of patients. Of those individuals, and we'll describe what refractory chronic cough exactly is, of those individuals, it's estimated anywhere from 10 to 48% have RCC, or refractory chronic cough. It tends to be more common in women than in men. That difference appears to manifest shortly after puberty, which may be a protective mechanism against aspiration during pregnancy. We see patients with acute cough, not infrequently. We see patients with subacute cough. That will not be the focus of this session, but rather focusing on patients with chronic cough as the topic of this one-hour session. So the European Respiratory Society actually places a very great emphasis on this disease process, or this symptom, depending on how you look at it. And just a couple of months ago, there was a number of individuals that spoke about this topic, and I was interested in learning that most of them were actually primary care physicians. And that does make sense when you think about it, because they will be the initial point of contact, whether it's an internist, a family medicine physician, or a physician assistant or nurse practitioner. And that's important, because they may be the only point of contact for these individuals. And as such, they will be the most important point of contact, because they will have more of a longitudinal history, they understand the social aspects of the patient's life, the impact on their family, and perhaps the impact on their work life. When we think about chronic cough, we're all pretty good, especially as pulmonary doctors, allergists, otolaryngologists, in terms of identifying potential associations, which include some of the things listed here, such as tobacco use, COPD, non-asthmatic eosinophilic bronchitis. The list is extensive, and I won't go through all of these. But the issue becomes, what is the burden of disease? And I know my colleague, Dr. Tran, will spend some time on this, but I'll touch on it shortly. First thing to notice is that chronic cough, or cough itself, can have a myriad of manifestations on various organ systems, ranging from case reports of bladder rupture, cardiovascular manifestations, such as syncope. There's some overlap with psychiatric neurologic manifestations. Tends to be a big issue in women. Peter published a paper not too long ago that showed how urinary incontinence is a significant problem, particularly in women. Cough syncope appears to be a large issue, particularly in men, which can have an impact on their work-life balance. There's been estimates that the esophageal pressure and the gastric pressure can range 300 millimeters of mercury during coughing bouts. So you can just imagine the number of manifestations these patients develop, and how significant those can be on a patient's life. Dr. Drake gave a nice talk this morning. I don't know if he's in the crowd, but this paper that he published not too long ago, and I thank him for allowing us to show this today, was a way of identifying why it may be that individuals with chronic cough actually have chronic cough. Is it simply due to their underlying asthma? Is it due to their, what we sometimes coin as upper airway cough syndrome? Or is there a different pathophysiologic, neurologic manifestation that is underlying their chronic cough? And what his study did is, and as someone that my fellows would tell you loves to do bronchoscopy, he looked at the airway epithelium, as well as the subepithelium in the airways of patients who were healthy controls versus chronic cough patients. Interestingly, what was found was that in the epithelium, but not in the subepithelium, the nerve density was much greater, and the nerve length was much longer. So, these individuals tend to have a higher concentration of nerves in the epithelial layer, which may explain why they have an exaggerated cough response. Dr. Irwin, who's an expert in chronic cough, published this paper in 1982 where he showed that in almost 100% of cases, an etiology can be identified. Well, I think all of us can agree that's not always true, it's not always easy. It may be easier in a study than it is in real life, but suffice it to say that there are cases where we look and we send these patients to, whether it's a GI specialist, an ENT specialist, multiple pulmonologists, and do an extensive set of tests, including spirometry, high-resolution CT scans, only to find out that they really don't have an underlying pulmonary pathology that would explain their chronic cough. And so, what is that? So, this is where it becomes interesting, and as a junior faculty member, I kind of have an interest in this process, because we see these patients and, you know, some of the fellows would argue, well, chronic cough is like the IBS of the pulmonary world. Well, that may be, but there's also a significant unmet clinical need for these patients from a diagnostic standpoint, as well as a therapeutic standpoint. So, when you have a patient that has chronic cough, defined as a cough of eight weeks duration or longer, who has either a lack of response to optimal therapy, and I know that can be subjective, but inadequate response to optimal therapy, or some of these conditions listed here have been excluded and the cough persists, then it is thought that that individual has refractory chronic cough, or as in Europe, they would call it chronic refractory cough. It's thought to be due to a distinct clinical syndrome that's related to vagal hypersensitivity. Now, in a quarter of those patients, an underlying pathology is not found, whether it's a pulmonary condition or non-pulmonary condition. And in this scenario, we would label these patients as having unexplained chronic cough. But the pathophysiologic neurologic underlying cause is thought to be similar regardless of what the patient has. So, and let's pay a little bit of attention in the next few slides on exactly what we think we understand, at least on the surface, with regards to the cough reflex arc as it applies to patients with refractory chronic cough or unexplained chronic cough. So, essentially, and I know there have been studies that have looked at the anatomic variations in the brains of individuals with chronic cough compared with healthy controls, and that is beyond the scope of this talk, so we'll focus mostly on the peripheral airways. And as Dr. Drake also showed this morning, I think it was a similar slide, where in the peripheral airway, there will be a stimulus. It tends to be an innocuous stimulus, something that tends not to cause an issue to many of us in the room, for example, who do not have chronic cough. Now, when you take that stimulus, similar to people that have chronic pain syndrome, patients with chronic cough will have an exaggerated vagal response to that stimulus. And that stimulus may be tobacco smoke. In a study, it may be ATP or capsaicin or a variety of other exposures. The effect is that the afferent nerves will carry that signal to the medulla, and then an effector signal is sent via either the spinal nerve, the phrenic nerve, or the vagus nerve to various organ systems, as noted here. It's important to note that the spinal nerve not only excites the expiratory muscles, but also has an impact on pelvic sphincters, which may explain incontinence, which we see in these individuals. We all remember from our first year of pulmonary fellowship when our attendings would tell us to keep the tip of the scope off of the main carina, the secondary carina. And that's because by doing so, you're eliciting a cough response, which is something we try to avoid when you're doing a bronchoscopy under moderate sedation. Those receptors are called the A-delta fibers. And these receptors are the more mechanosensitive receptors that are actually protective. These are the receptors that we want to keep intact when we think of future potential therapeutic options. It's the C-fibers that are the fibers that we want to pay our attention to. These will be the unmyelinated fibers that tend to be in the epithelial layer of the airways, which I showed earlier. They respond to different exposures, which in this day and age can be wildfire exposures, biofuel, other pollutants, bradykinin, tobacco smoke, cold air exposure, and a myriad of other potential triggers. These are in the peripheral airways. And essentially what we see is that people with refractory chronic cough or unexplained chronic cough can be exposed to very innocuous stimuli and have an exaggerated response. And so Dr. Mazzoni, I believe, is a, well, I know, is a cough expert from Australia, noted very elegantly a couple years ago in a patient cough conference when he mentioned that the nervous system in these individuals acts as an amplifier. It's exaggerating in terms of carrying impulses to the brain stem. So what are the potential targets? I won't spend too much time on this as Peter, who's done numerous studies on this topic, is going to educate us today. But suffice it to say that ATP was looked at by Jeffrey Bernstock in the 1970s. So five decades ago, there was a researcher that looked at ATP in causing changes in the P2X3 receptors that could potentially cause a cough response. And so the idea might be that we need to focus our attention on the C fibers. And while we have some drugs in the pipelines that are looking at the P2X3 receptors, it's possible that there's a myriad of other receptors that we haven't yet touched or yet studied, which kind of lends to something that we do with patients who have asthma in terms of having different endotypes or patients with COPD, where we need to take a targeted approach or personalized approach to medical treatment of chronic cough. So depending on the disease state, there's varying degrees of cough. We're not very good at portending how well or poorly a patient will do. I know there's research being done on cough monitors. My hope is that, similar to a six-minute walk test, cough monitors may be able to give us some, shed some light as to how a patient will do prognostically. That would be an interesting area of study. And then having this new term or definition that's been supported now by multiple societies, I think helps us understand the disease a little bit better. And while we yet don't have any FDA-approved drugs in America, we can at least offer some explanations to our patients, which sometimes can be very reassuring, at least to know what the underlying cause is to their cough. And then hopefully in the future, based on these findings, we will be able to find therapeutic avenues that Peter will touch on today. Thank you very much. Good afternoon. I'm from Virginia. So the topic for me today would be chronic cough and bronchiectasis. So two things that I can think about that's common in the two diseases, almost 50% are idiopathic. So the topic today is going to go through a little bit of thoughts here to see the relationship between cough and bronchiectasis, think about if I can talk about how the pathophysiology may work for the cough and bronchiectasis, what we know from the cartoons and what may be going on inside the body. Also talk about some of the workup that we can do about this chronic cough and bronchiectasis and think about how to manage them. So it's fairly common, you know, a lot of people with bronchiectasis have cough as a presentation. So about more than 90%, but 2% to 4% of causes of chronic cough are attributed to bronchiectasis. So the validated tool to measure the severity is the LCQ and that has been not very commonly used in clinical world or in our clinics or in our clinical trials. So that's a very good low-hanging fruit that we can use for our practice as well as towards the future of clinical trial and it will help objectively, potentially associate phenotypic expression of the chronic cough as well as the disease that can be annotated with that cough, which we have not been able to attribute. For example, asthmatics may have a certain type of cough or people with COPD or other causes, et cetera, may have a certain characteristics of cough that we don't know. Cough frequency can be prognostic, as we know, and I'm going to convince you with that. In the etiology of bronchiectasis and cough intersect, but we don't know where and when and how. So there are certain things as we look in the prognostic classification for bronchiectasis. So the markers that can help us determine that would be if you have worsening symptoms or worsening HRCT presentation or score, the worst could be clinical expression of this cough in people. They could have increased sputum volumes, sputum purulence, or culture positivity with certain bugs like pseudomonas, as well as the bronchiectasis severity index has been associated as a marker that can be annotated the worst. It will be the worst. The cough could be the worst, could be the BSI in these patients. So cough can be a blessing and cough can not be a blessing in these patients. So, you know, as clinical practitioners, we try to ask the patient not to use antitussive, not to suppress the cough with the risk of worsening infection. So what are the positive sides? You can have increase in mucus clearance. You can have less potential inflammation and infection. You will have reduction in bacterial load or colony counts and potential reduction in exacerbations and improved quality of life. What are the potential downsides? As my colleague here mentioned, could lead to urinary incontinence, also lead to more dysfunction headaches and other complaints like more subjective and objective complaints. So the question is, how can we associate the cough in bronchiectasis, whether what is the chicken or the egg? So if we go through this vortex cycle of potential inflammation infection, you know, it's hard to say why do certain people of COPD develop bronchiectasis and others don't? Why do certain peoples of asthma develop that and do it? In some countries, presentation of bronchiectasis and asthma could be just bronchiectasis, whereas in other parts of the world, we see that as a potential downstream phenomena in which they first had this disease and that led on to potential bronchiectasis. We don't know. So potentially, whatever it is, whatever it causes, I mean, it's hard to see that 50% of the disease that we attribute is idiopathic, that we don't know. Despite all the workup. So we think some insult happens either due to immune deficiency leading to mucus buildup, airway ciliary dysfunction, mucus collection, potential infection and inflammation, leading on to hypersensitivity of the nerves and leading to more cough. So in this cartoon here, this author has tried to show provoking factors, more etiological, therapeutic, and microbiological and neuroimmunological factors. The plus sign here in the white circle has evidence where it leads to worsening of the cough. The negative circles here have the evidence where it did not lead to potential improvement in the cough in those particular patterns. And the gray are thoughts. They're not evidence-based that they can make the cough worse. So looking through it, if we see the ideological infections can make the cough worse, there's evidence. How about the things that can make the cough better in bronchiectasis, airway physiotherapy. Sorry, physiotherapy will make the cough worse. And so positive factors mean worsening of the cough. And the negative means what things can improve, like antibiotics, vitamin D, and statins. And similarly, going through the other things, and we are going to, because of the lack of the time, it's not possible for me to go through each step. But we'll go through the slide here next. So the thoughts here is like what can provoke a clinician to think about as the first presentation that the cough is because of bronchiectasis. So if a young guy has these weird bugs, or young woman, you can think about potential bronchiectasis. Also, they have associated infertility, malabsorption, sinus disease. You can think about that they could have potential bronchiectasis. And a cough without smoking history. And just not to show everybody here that how in the workup a CT will look like, but your periphery airways will be going all the way instead of pruning and disappearing toward the end. They go all the way to the end. And then in the red arrows and the blue arrows is a signaling sign in which your artery is as big as the airway accompanying at the lower lobe in this patient. Just to show you various forms, which also has the severity prognostic factor. So the first thing is the normal airways right here. And then you could have the cylindrical bronchiectasis, and then the varicose bronchiectasis, and then the cystic bronchiectasis. Each one of them have a severity index in a stage-wise fashion that we want to prevent. So we don't have the audience response questions. So we'd like to ask any fellows to scream out the diagnosis here, just looking at the CT. So we have this patient. Excellent. So simple like that, looking at the genetics of this on the right. So that would provoke an association like PCD with cytosine versus. So how can we work up an approach? So typically, we will take a good history. Then we will look into doing some CT scan and sputum cultures, PFTs, and then try to work up the etiology of this chronic cough and bronchiectasis and try to annotate a diagnosis which can actually improve some of the management that we can do. These are the ERS guidelines for bronchiectasis, and they are talking about what are the things that we can do for bronchiectasis. Like we can try to treat chronic infections. So if someone has a first-time growth of a microorganism like pseudomonas, we try to eradicate. And if they have a recurrent growth like mucoid version, then we try to chronically suppress them. You can also use airway clearance, obviously, which is 50%. Most of the treatment, we typically do some hypertonic or some of the PEP devices, whatever the patient can handle, like high-frequency chest wall oscillation. Some localized bronchiectasis, we can do surgery. We can also have some rehab. Inflammation for a long time was thought to be used in people like really with inhaled steroid and asthmatics, or people who would have certain association like ABPA. But nowadays, you may have heard the drug like DPB1 inhibitor, bransucatib. So that is coming up, which is a neutrophilic inflammatory marker. So we'll have some role here to target this pathway. And we talked about the airway clearance as a potential strategy. So physiotherapy can target significant amount of chronic cough and bronchiectasis and leads to improvement in sputum production and decrease in the frequency of potential long-term cough. In this paper, authors were trying to look up for the NCQ and the FPFT improvements on when they did this twice-daily physiotherapy as compared to no physiotherapy. So clearly, people who are doing some sort of routine airway clearance will have more improvement in cough symptom as compared to people who don't do any forms of physiotherapy. Again, in this paper, they also showed that people who did some sort of airway clearance, they were able to have less fatigue and improvements after physiotherapy on all these parameters of chronic airway problems like cough as well. And similarly, in this paper, they are also talking about the high intensity inspiratory muscle training in bronchiectasis. So this led to some improvement in how the people can control their cough, particularly in social environments. In this slide, I tried to show you treatment approaches. So if we can try to come out with a diagnosis, then we can try to target the specific treatment. So if we have a certain growth of an organism, we have certain things to do, like inhale antibiotics, we can also do chronic macrolides. Always have to check for NTM before we do macrolides. We also try to look for the A and B cultures at least twice a year. So that's the suppressive therapy and approach. There are a couple of inhale antibiotics that are already approved, like Tobi and Cayston and Colistin now increasingly coming up. More so data is on CF world, but also there's some data on the non-CF bronchiectasis as well. And then we also target some of the specific diagnosis based on what we find out. Again, the BTS guidelines here talking about if you have pseudomonas, you can do chronic inhale antibiotics. If you have non-pseudomonas, the evidence may actually go for both pseudomonas and non-pseudomonas now with more recent data. And that is going to be revised, that the macrolides can be used as well for both pseudomonas and non-pseudomonas. They are easier to take than chronic inhale antibiotics. So just showing up here the antibiotic data, the chronic Tobi is one of the things that people can use to improve people with chronic cough, reduce the frequency of exacerbations, and potentially have some improvement in the PFTs. So if we have less cough, potentially less exacerbations and improvement in the prognosis of people with bronchiectasis. Azithromycin data, three trials really embraced, BLESS and BAD trial, all showed that azithromycin helps in reduction in exacerbations. Vitamin D3, so this is something, vitamin D3 has a role in immune modulation, so it can help with the potential role in regulation and potential control of coughs. In this study, people felt like people who took vitamin D3 in chronic cough actually had less exacerbations as compared to people who are not on vitamin D3, interesting. Statins, again, do not have any guideline evidence, no strong evidence, but in this there was some trend that there was some reduction in cough questionnaires or score in people with chronic cough and bronchiectasis. So if your patients are there, we can potentially look for those patients who are taking statins and potentially have bronchiectasis. Do not have any evidence for antitussives, so I will discourage that, but there's no real evidence and people have tried to use those. Again, I think Matt was earlier, a colleague, mentioning here about the cough monitors. I think that's going to come out in the clinical trials to use as a potential monitoring parameter for people who have bronchiectasis and a cough as an endpoint or end tool for clinical endpoints for bronchiectasis, which will be good to know. So again, in this very quick presentation of 10 minutes or so, I tried to give you disease burden as present in bronchiectasis. these are some of the things that we don't know and can be potentially be discussed in more in a research environment for people who have chronic cough and bronchiectasis. Can it be used as the endpoint? Also, can it be associated with certain phenotypes? So bronchiectasis is diagnosed in approximately 4% of patients with chronic cough. CT scan of the chest is the best test to establish. Most cases of bronchiectasis in adults are idiopathic, but in the absence of an obvious cause, a diagnostic evaluation for an underlying disorder should be performed. We have some bronchodilators that we can use. We have some antibiotics, physiotherapy, and surgery in rare cases with localized cases. I think that should be it. Thank you very much. Good afternoon. I just wanted to remind everyone that I have a couple of audience response questions, as well as we're gonna have more questions at the end of this session. So we'll save all the questions for at the end. I'd like to express my gratitude to Dr. Nawari, who's given me the honor of participating in these discussions. My name is Lynn Tran. I'm from University of California, San Diego Health, and I have no financial to disclose. So as I mentioned before, my aims is to discuss some of the impact of chronic cough to our patients and their families, and review some of the management of chronic cough according to the 2016 CHESS Guidelines. So let's start with an audience response question. A 62-year-old female presents to your clinic complaining of a chronic cough. She's been coughing for 18 months. Patient is very frustrated and said she tried everything her primary care doctor prescribed, which includes inhaled corticosteroid, proton pump inhibitor therapy, a variety of nasal spray. So in evaluating and treating patients with chronic cough, which of the following statement is true? A, women and men have similar threshold of maximum tolerable dose of inhaled capsaicin-triggering cough. B, women with chronic cough reported a similar quality of life than men with chronic cough. C, epidemiologic studies expression scales is higher in women than in men with chronic cough. Or D, urinary incontinence is one of the primary factors impacting the quality of life in women with chronic cough. So that's great. The majority of people picked the right answer, which is D, urinary incontinence is one of the primary factors impacting the quality of life in women with chronic cough. So on the topic of chronic cough epidemiology, a comprehensive system review and meta-analysis in 2015 estimate the global prevalence to be approximately around 9.6 or 10%. It's pertinent to know that this number is divided from the average regression analysis, and it may not capture the true prevalence due to the heterogeneity in the definitions of the chronic cough that across the studies. However, there's appeared to be a higher reported prevalence in developed nations, which could be attributed to most chronic cough studies are being conducted in these countries. However, irrespective of the study design, whether it's observational or randomized control trial, research on chronic cough frequently indicates a notable gender discrepancy with female participant outnumber the male with the ratios from three to one or four to one. This trend may be evident in the patient demographic observed probably in your cough clinic. So this pronounced in the prevalence difference between female and male can be attribute to several factors. The first is being female exhibit a heightened cough reflex in comparison to male. Research has demonstrated that female possess an increased sensitivity in the transient receptor potential channels presence on the vagal C-fiber responsible for mediating cough. This result was demonstrated to studies where participants inhale capsaicin to trigger cough, and women have lower threshold of maximum tolerable dose of the inhaled capsaicin. Furthermore, there is a unknown reason why, but the presence of vocal cord dysfunctions is more prevalence in female compared to the male counterpart. So research also consistently shown that chronic cough adversely affect the physical, emotional and psychological wellbeing of patients, both genders. So when assessing the burden of chronic cough through the quality of live questionnaires, the impact appears more pronounced in female than in males. For instance, women frequently report severe physical symptoms such as nausea, retchings or the instances of incontinence. These are more often in female than male. Nevertheless though, the epidemiologic study depression scale scores are comparable between women and men who suffer chronic cough. So chronic cough affects various aspects of patient's wellbeing, as said by my colleagues before. Physically, it leads to symptoms like sleep disruptions, syncope, vocal hoarseness and headaches. From a psychological standpoint, patients often feel embarrassed, they feel frustrated and a lot of anxiety. There's also this lurking fear that they are feeling that they are having some terminal conditions such as like malignancy. But the social economical implications of chronic cough are also very significant. Patients often avoid going out or attending social gathering because of their cough. And subsequently, their relationship with friends and families are ineffective. So economically, patients also reported facing job loss, decreased productivity and strained in their financials, wellbeing from all the medical bills that they get from frequent doctor visit, the costs associated with multiple diagnostic tests and also in the barrage of treatments that they try to get rid of their cough. All right, let's shift gear a little bit to discuss about the management. We'll start with another audience response questions. A 62 years old female present to your cough clinic complain of a cough for 18 months. Her cough is nonproductive and at times causes her to have urinary incontinence. She denies any post nasal drip symptoms. She tried varieties of antihistamine, decongestants and over-the-counter cough suppressions, medication without effect. You review her medical records and found that she has a normal chest X-ray, pulmonary function test, negative pH monitoring and EGD. She saw a pulmonologist prior and had a normal high resolution CT chest and unremarkable bronchoscopy with negative eosinophils in the BAL. Her physical exam is unremarkable. Her inhaled nitric oxide is two part bromelains. According to which of the following is the next reasonable step in the management? Okay, A, initiate inhaled corticosteroid. B, a trial of gabapentin. C, start Omeprazole. And D, start antihistamine or decongestion therapy. All right, everybody got the right answers. Try of gabapentin. So per 2016 chest guidelines on the treatment of chronic cough, there are a few pivotal strategies. The initial step involve establishing the diagnosis and then there are a number of strategy including speech therapy and language interventions and some medications such as gabapentin and also referral to specialized cough clinic and if suitable, enrollment in clinical trials. So I will go through this quickly. The diagnosis explained of chronic cough is established through a process of exclusions. As the audience responds, questions give you the clue that we often exclude upper airway chronic syndrome, also known as ponasal drip, asthma, and then also excluding the non-asthmatic eosinophilic bronchitis and GERD. So those are the simple step to involve in. So for non-pharmacological strategy that stands out in the recommendations is the referral for speech interventions by a speech, not a qualified speech therapist. This interventions or recommendations stem from a single-blind randomized placebo-controlled trial. In this study, 87 patients who were resistant to non-conventional cough treatments were allocated either to specialized speech therapy program or placebo and the components of the intervention arms include education and strategies to reduce cough and strategies to reduce laryngeal irritations and also psychoeducational counseling. Both group had four sessions with a qualified speech pathologist. 88% of the treatment group had successful outcome versus only 14% in the placebo group. And the successful outcomes were defined as a significant reductions in various symptoms scores, such as cough, breathing, voice, and upper airway. So another test guideline is the endorsement of gabapentin as one of the pharmacological intervention for chronic cough. Gabapentin is a neuromodulator and it has shown efficacy in reducing neuropathic pain characterized by central sensitizations. So this recommendation is based on one randomized double-blind placebo-controlled trial. In this study, 62 patients were randomized to gabapentin or placebo. The gabapentin was started on 300 milligram daily and increased to a maximum dose of 1,800 daily as tolerated and subject in a gabapentin group had a significant improved cough-specific quality of life compared to the placebo. And the difference is 1.8 in the score that translated to a number needed to treat of 3.5. And however, almost a third of the gabapentin group also experienced side effect, mainly nausea and fatigue. So other notable recommendations by 2016 test guideline are the guideline advanced against the prescriptions of inhaled corticosteroid in the absence of positive findings of bronchial hyperresponsiveness and eosinophilia. Proton pump inhibitor therapy is not recommended if the evaluations for GERD return negative results. If a specialty cough clinic is accessible within your vicinity, the guidelines advocate for patient referral to those clinic for specialized care and consider referring patients for relevant clinical tries as an option for cutting-edge treatments that my colleagues will be presenting today. All right, thank you. Well, thanks very much to Matt for organizing this excellent session. So my task is to update you folks on the P2X3 receptor antagonist drugs that are currently in clinical development as hopefully the first ever cough drugs available soon. I'm Peter Dispingaitis. I'm from Albert Einstein College of Medicine in Montefiore Medical Center in New York. These are my disclosures. So as I said, I'm gonna talk about the soon to be available first ever chronic cough drugs. But before that, even though Matt in his excellent introduction covered this, it's important for us to know what we're talking about in terms of definition. So chronic cough and refractory chronic cough bear some repeating. So we as pulmonologists have been following this paradigm for decades. And that is how long a patient has had cough informs us as to what the likely etiologies of that cough are. Acute cough is almost all due to acute viral upper respiratory tract infection or common cold. Subacute cough is usually a prolonged acute cough post viral. But once a cough becomes more than eight weeks, now eight weeks of course is somewhat arbitrary, but it does inform us that once a cough is more than eight weeks old, it then becomes quite likely that that cough is due to one or more of these underlying etiologies that's been discussed already. Now refractory chronic cough means that it's a chronic cough. Now definition of chronic cough is you've had a cough for eight weeks and one minute, that's chronic cough. There's no other discussion. But refractory chronic cough means that you have a chronic cough that has failed to respond to adequate and appropriate empiric therapeutic trials against the common underlying causes, okay? I put those italics in because it's so important. And this one slide can be the topic of a 45 minute lecture, which for me, it frequently is, but it's important to really understand and appreciate that we can't render the diagnosis of RCC until we've properly ruled out underlying causes. So for example, upper airway cough syndrome, first generation, newer generation antihistamines don't work, loratadine, cetirizine, fexofenadine are worthless for a cough. You have to use an oral first generation antihistamine. You cannot rule out asthma because your patient said that somebody gave them an inhaler they used last year for a week or two, they weren't sure if they used it right, but the cough didn't get better, so it can't be asthma. Okay, that is of course an absurdity. I always do a prednisone trial and reflux is a tough one. You know, the first step in reflux is two months of a PPI, half an hour before breakfast and dinner with a whole bunch of lifestyle measures. So until you've done all that, we can't render a diagnosis of RCC, but the reason it's so important for us to understand what RCC is and properly get to that diagnosis is that most of the drugs in the pipeline as we speak are gonna be indicated for and labeled for RCC. Some of the new drugs are being looked at for IPF cough, but most of them for RCC cough. So thankfully the last decade has been really busy in the world of cough, there's been a lot of work, and it's mainly because we've learned so much about the mechanism of cough, which Matt showed in his intro, and once you know about receptors and ion channels that are relevant to the mechanism of cough, you can then look for antagonists or agonists to those receptors and ion channels to help you find potentially molecules that can be cough drugs. So for the sake of this talk, I'll be speaking just about the P2X3 antagonists, but those are by far the furthest along in clinical development. So in terms of the mechanism of the P2X3 receptors, so P stands for purinergic. So these P2X3 receptors, actually they're ion channels, they're ubiquitous in the sensory nerves of the body, including in the airway, and the presence of ATP within the airway, and excessive ATP, which happens with airway inflammation or other types of airway injury, the increased presence of ATP within the airway stimulates these P2X3 ion channels to then incite the vaguely mediated afferent signal to the brainstem to induce the motor events of cough. Now the P2X3 ion channel exists in two forms. There's a P2X3 homotrimer, where all three components are the same, and there's a P2X2 slash three heterotrimer. Now the importance of this will be evident on the next slide. So when we block the heterotrimer with the P2X3 antagonist, that is what gives you the suppression of cough. Now interestingly, the P2X2 three heterotrimers involved in the sense of taste. So an interesting side effect of these P2X3 antagonists is that some patients have either a diminution of or an alteration of their taste. So this one figure summarizes multiple phase two studies looking at jefapixan, the lead drug in this space has already completed phase three trials. And the initial study, the proof of concept study of jefapixan was published in Lancet back in 2015. And a massive dose was chosen, 600 milligrams twice daily. Those 24 subjects all lost their taste and freaked out, but, and 25% dropped out of that study. So multiple phase two trials were done subsequent to see how low a dose you can get to that still remains effective for cough, but finding that sweet spot, so can you maximize antitussle therapy, but minimize the taste effect. So this red line here is objectively measured cough counts with a monitor. And as you see going from 600, 200, all the way down to 30 to 50 milligrams, you retain that antitussle effect. The green blue bars show taste alteration, and you see it kind of comes way down here. So based on these studies, a 45 milligram dose and a 15 milligram dose of jefapixan were chosen to go forth into phase three. So in early 22, last year, we had publication of the first ever phase three study for a chronic cough drug in Lancet. These studies were called COUGH1 and COUGH2. They were parallel phase three trials. And what did we see? So we had learned from phase two that cough studies are often riddled with a very large placebo effect, very similar to what's found in pain studies. So in this first ever phase three study of a P2X3 antagonist, there was a unexpectedly large placebo effect. But despite this large placebo effect, the larger 45 milligram dose of jefapixan still had statistically significant cough suppression beyond the large placebo effect. The 15 milligram dose did not, and therefore the 45 milligram dose is what's put forth before the regulatory agencies for approval. Now, all of the studies done for jefapixans had sort of arbitrarily said, well, chronic cough, let's just say you've had to have the cough for more than a year. Because they wanted to make sure these were really chronic cough patients. But you can have cough for 11 months, eight months, nine months is still chronic cough. So a very relevant question to ask was in this phase three B study that was just published looking at folks that fit the criteria for RCC but have had the cough for less than a year. And in this study, the median duration was about seven and a half months. And again, now here we had only an objective measure, the previously discussed Lester cough questionnaire, which is a published validated cough questionnaire with a published MCID. The 45 milligram dose of jefapixans, again, was statistically more effective than placebo. So old chronic cough and new chronic cough all work. So jefapixans was the lead compound. They completed phase three studies, but there were multiple other molecules being looked at. And the reason the sponsors of those molecules were developing these other drugs as potential medications is that these molecules were felt to be more P2X3 specific, the homotrimer for cough, and therefore less effect on the P2X23 heterotrimer. So the feeling there was that these drugs then would have less of a taste effect. And in fact, phase two and phase three study, phase one and phase two study showed that that was in fact the case. Unfortunately, the Bayer and Shinogi molecules are no longer being looked at, but BLUE5937 did complete phase two B studies. BLUE now has a chemical name of camlypixans, right? So it's jefapixan, camlypixans. The pixans is the end name. They finished a phase two B trial called Soothe. And in Soothe, they looked at three doses of the drug, 12.5, 50, and 200. And what they showed looking at objectively measured cough frequency with the same instrument as in the prior study, both the 50 and 200 milligram doses had a 53% reduction in objectively measured cough, 34% placebo adjusted. And again, the 50 and the 200 milligrams performed very similarly, and therefore the 50 milligram dose is what's being carried forward into phase three studies. So I mentioned the theoretical thought that if you're more P2X3 specific, you should have less of a taste effect. And in fact, this was borne out looking at camlypixans at the 50 milligram dose that's in phase three right now, the incidence of taste effect was quite low in the six to 7% range. So based on that phase two B Soothe study performance, camlypixans is now in phase three. They started enrolling in January of this year, so 10 months ago. And the two studies will be very similar to the COUGH1 and COUGH2 studies that jifapixans went through. 12 weeks of therapy, 52 week follow-up, 24 weeks of therapy, 52 week follow-up. So we're hoping to have jifapixans very soon. We're hoping to have camlypixans in the not too distant near future. That will hopefully give us the first ever drugs for chronic cough, because there's never been a drug for chronic cough approved in the history of United States. The last cough drug of any type that FDA approved was back in 1958, benzonatate. But there's never been a chronic cough drug approved. So we are hopeful. And then beyond the P2X3s, as I showed in my earlier slide, there are other molecules being looked at in phase two. And we'll be hearing about those in the years to come. So thank you for your attention. We will bring all the speakers up for Q&A. Thank you.

refractory chronic cough

new drugs

chronic cough

underlying causes

women

primary care physicians

hypersensitivity

treatment options

cough reflex