Reclaiming Control in Refractory Chronic Cough: Evidence-Based, Patient-Centered Diagnosis and Care

Dr Michael Benninger (Cleveland Clinic): So I am going to talk a bit about the burden of RCC, which tends to be a huge issue for many, many of our patients. You will see that in a patient video that we will show.

[00:06:37]

Patient Perspective: Experiences With RCC

Robert Kindig: I got out of the Air Force in 1988 and I have been doing technology support since then, which requires a lot of phone time, a lot of talking to people, and the cough constantly got worse as time went on. It makes it difficult to be efficient with the customer to talk to them, and it is unfortunate to have to hold the phone away and cough. The customers I am sure get disturbed by that and me a lot more than they do.

It is difficult when you are going out with friends even to not talk because you do not want to start coughing in the middle of them. It affects you a lot. Back in the '90s I was going through allergy testing and everything that they could do at that time to find why I was coughing, did not really link it to a result of my talking that would cause the cough. In the early 2000s, I was diagnosed with the neurogenic cough, but at that time they said they could not do anything about it.

I decided recently in October of 2024 to see if technology has changed. I visited a specialty clinic and the doctor there started back over with testing. Went through allergy and x-rays and all the normal tests you would do. He also concluded it was a neurogenic cough. The difference was this time he said there was a treatment available.

[00:08:30]

Epidemiology of Chronic Cough

Dr Benninger: I think many of you relate to that patient's story when it comes to this. The epidemiology of chronic cough. It affects 10% to 12% of the world's population. There is a female predominance in almost all studies. Typically, presents later in life, most common in the 50s to 70s. More than two thirds of patients are older than 50 and 20% are older than 70. Interestingly, smoking and air pollution are risk factors. It is never smokers. Plus air pollution show an increased risk for cough and phlegm production.

[00:09:10]

Refractory/Unexplained Chronic Cough

When we look at patient scenarios, chronic cough has no diagnosable cause and we go through a myriad of diagnosis to try to figure out and testing, to try to figure out why they have a cough. Potentially, underlying cause of cough are usually been treated. They have been through asthma treating. They have been treated for reflux. We like to call it laryngeal reflux. In laryngology, they have been treated for allergies. Their medications do not induce cough, but the cough persists.

The term unexplained or refractory chronic cough or UCC is another term. Basically, it is those group of patients that may have reasons to have cough, but those have been adequately evaluated and treated and the cough persists. 5% to 10% of those who have already had a chronic cough. It is thought to be largely driven by cough reflux hypersensitivity, many different potential pathways, and Peter will talk about those a little bit later.

[00:10:20]

Healthcare Resource Utilization and Care Disparities in Chronic Cough

Huge amount of healthcare resources go into chronic cough. 5% to 6% of patients have had more than 3 consultations in the past 12 months. I have patients that have been evaluated 40 times and have traveled all over the country to have this evaluation. Many of these people have had these for multiple years. It accounted for 50% of physician consultations for cough.

Usually, what happens is they see a bunch of different specialists, there is multiple opinions, oftentimes testing is repeated, which further increases the cough. Then there is this polypharmacy where there is on all different medications. Maybe all at the same time, and we cannot really differentiate which one of those are working or not working.

There seems to be healthcare disparities. Higher prevalence in women and we already know that there is a higher prevalence with racial, ethnic, and socioeconomic situations with patients with respiratory injury illnesses. Factors including in the disparities, including smoking prevalence, air quality, and care access. Chronic cough in adults over than the age of 74 or 70, and the poorest quintile tends to be much, much higher than the wealthiest quintile.

[00:11:46]

Patient Perspectives: Impact of RCC

Patient perspective. I am not going to read all these, but clearly it hinders communication. It is embarrassing, it is frustrating. They worry about it. There is a reduced quality of life. Many women, particularly with these paroxysms of cough, will have incontinence, which makes it even more difficult for them to get out and get around.

Many things can trigger this including smoke exposure, chemicals, changes in body position, speaking and singing, and exercise. Oftentimes it may become more frequent and severe over time. Only about 40% of people show improvement of symptoms with medications. Many, many patients, 70% are frustrated by resistance of their symptoms and the lack of effective treatments. You can look at the comments to the right, which is very common in our patient population.

[00:12:42]

          McMaster Cough Severity Questionnaire (MCSQ)

There is a McMaster's Cough Severity Questionnaire and we will talk about other questionnaires going forward. This allows us to get an assessment of how often, how severe, what you do to control your cough, et cetera.

[00:13:02]

          Patient-Prioritized Outcomes: What Do Patients Want From Chronic Cough Treatments?

We know that patients that do have cough want the treatment. Most improving cough symptoms over emotional wellbeing, it prioritize. It takes over their lives. It is what they think about all the time and they have variability in goals. Many people it is just reduction of cough. Getting to be able to sleep through the night. Getting to be able to go to dinner and that cough during dinner. Most patients actually feel that a reduction in cough frequency would be in a meaningful improvement based on this survey.

[00:13:43]

          Posttest 1

This is a pretest question number one. The 60-year-old woman with chronic cough despite effective treatment. Her asthma reflux, her cough worsens, and she is diagnosed with chronic refractory cough. She had 5 to 10 spells a day. Difficulty breathing and faintness, she would like her treatment. What is the answers?

The correct answer. I do not think we are going to get those at this point. Here we go. You could see below that the correct answer is B, which most of you got correct. Most consider 25% to 50% lower cough frequency and important improvement. We have a couple of minutes, why do not we see if Peter and Michael may have some comments. Is that patient a typical patient for you or do you see people with much more severe symptoms? Michael, what do you think?

Dr Michael Blaiss (Medical College of Georgia): Yeah, I think this is very typical. These patients have been suffering for a long time. They have been trying lots of different treatments and in fact nothing has helped them. Again, I think they are very frustrated. Many times they have gone to outside the typical medical care. They have gone to homeopathic medicines, other types of things because they are so frustrated.

I think one of the things we have to realize on these patients is that we have to be really empathetic with them and really understand that this is not just a cough. That they really are suffering with the condition and with some of the tools we will talk about, there is more that we can do for these patients now and hopefully much more in the future.

Dr Benninger: Peter, when you see patients with cough, what bothers them the most?

Dr Peter Dicpinigaitis (Albert Einstein College): It is a whole range. The most common type of patient we would see would be, as you mentioned, a woman in her 50s or 60s. Two thirds women come to cough centers like mine and you made a very good point. They are not looking for zero cough. They are just looking to make the cough not in the forefront of every minute of their waking day and just in the background. I will make 1 point in women urinary incontinence is very, very common. In fact, we did a study showing that 62% of women with chronic cough report cough induced stress urinary incontinence.

They will not tell you unless you ask them because they feel that it is something rare to them. You can make a cough only 25% or 50% better. That could almost or completely eliminate the urinary incontinence because the urinary incontinence usually comes only with severe very forceful prolonged episodes. That is just 1 example.

If you can buy somebody 2 hours of coffee free period, then maybe they will go to a restaurant, a concert or the church for the first time in 20 years, which is not unusual for patients of mine. We do not need perfection. We do not need zero to make a major change in the lives of these patients.

Dr Benninger: We have just completed a study. It is going to be presented soon and we have actually looked at sexual function and it has a dramatic impact in patients and their sexual function. You can imagine how unattractive it is to be coughing in somebody's face when you are trying to be romantic. It really impacts a broad swath of their life from church to going out to dinners to work. It is pretty impressive how impactful unexplained or recalcitrant chronic cough can be for patients.

With that, I am going to turn it over to Michael and let him continue the discussion.

[00:18:04]

Detecting RCC: Guideline-Based Diagnosis and Assessment

Dr Blais: Thanks, Mike. What we are going to do now is look at guideline-based diagnosis assessment of our patients with chronic cough. As we will see to get to that diagnosis of refractory chronic cough, it is a diagnosis of exclusion. There is a significant workup that needs to be done in these patients to in fact look for possible causes of their chronic cough.

[00:18:34]

          CHEST Guidelines

Many guidelines have been published over the last several years from around the world looking at diagnosis and management of patients with chronic cough. The 1 I think we use the most in the United States comes to us from the American College of Chest Physicians published in 2018 in their journal.

What we can see here over on the right is the algorithm as far as the diagnosis of this condition. What I would like to do right now is take a deeper dive and look at this and go over how in fact we may want to evaluate these patients using this particular guideline.

[00:19:16]

Initial Assessment of Chronic Cough

We will look at the initial assessment of patients with chronic cough. As with all conditions, we need a detailed history. We need to know what may have triggered the cough to begin with. What is the length of time that they have had the cough? Is it truly greater than 8 weeks so they have chronic cough. We need to know any of the triggers that they notice. It may in fact be triggering their cough. Is it due to some environmental exposures or occupational exposures that tend to lead to spasms of cough?

Family history can be very relevant here. There is a strong family history of allergies and asthmas. We will see those can be causes of chronic cough in the patient population. Obviously, if that patient has a smoking history is that could be a large group that in fact can have chronic cough. We need to know again what other evaluations and treatments they have had. As Mike mentioned, maybe we do not have to repeat some of these types of things. It gives us an idea of where to start.

Then we need to know all the medications that they are taking. A prescription, over the counter, herbal types of medications. We need to look for medications that could cause chronic cough, the major 1 being ACE inhibitors.

[00:20:38]

          Red Flags

When we are doing this initial evaluation, we need to look at these red flags, and these are conditions that can be life-threatening for patients related to chronic cough. If they are having hemoptysis or if it is a smoker that is over the age of 45 with a new cough, or if that patient has prominent dyspnea, especially at rest or at night. Maybe we are dealing with congestive heart failure leading to chronic cough, or they have systemic symptoms like fever and weight loss that may be related to a malignancy. Trouble swallowing when eating or drinking. That could be a neurogenic problem. That could be esophageal malignancy, recurrent pneumonia, and any patient that has an abnormal respiratory exam, abnormal chest x-ray that coincides with the duration of their cough.

[00:21:28]

The “BIG 4”

Now let us say we have done all this initial evaluation. We have gone through the red flags, nothing has come up. They are immunocompetent. They do not smoke, Their chest x-ray is normal. We are left what I call here the big 4. The 4 most common causes for chronic cough that we see in the population and that is:

• Upper airway cough syndrome, which we used to call postnasal drip syndrome;
• Asthma;
• Non-asthmatic eosinophilic bronchitis; and
• Gastroesophageal reflux disease.

[00:21:59]

          Evaluation of the “BIG 4”

Now it is very important that we work up the patient for all of these conditions because it is not uncommon for a patient with chronic cough, in fact, to have more than 1 of these conditions. We can start with upper airway cough syndrome. That could be due to chronic sinus problems, nasal problems, both allergic and nonallergic.

You may consider sinus imaging or nasopharyngoscopy, allergy evaluation, and if not clear may want to try empiric treatment. Here we usually use a first-generation antihistamine due to its anticholinergic effect and may also add an oral decongested.

Next we have asthma. We know the typical symptoms with asthma. Again, some patients only cough with asthma. Obviously, the important role of spirometry with pre and post bronchodilator. We may need to do a bronchial provocation challenge to determine if there is asthma allergy evaluation again, and we could talk about empiric treatment when it is not clear. Maybe a burst of oral cortical steroids with a slow taper or starting the patient on inhaled corticosteroids.

Then non-asthmatic eosinophilic bronchitis. This is also an eosinophilic lung condition as asthma can be, but these patients do not have airway hyperreactivity. They may have some of the same symptoms that we see in asthma. As far as diagnosis, one could look at sputum and look for high levels of eosinophils. Also, they can have elevated exhaled nitric oxide as we can also see in some asthmatics. Allergy valuation may be indicated. Again, empiric treatment in fact would the same that we would use for asthma.

Lastly is gastroesophageal reflux disease. In fact, is there a relationship in the patient's symptoms of chronic cough associated with symptoms of reflux like heartburn? Some of the things that we would do here is usually give a trial of proton pump inhibitors, usually beginning at a dose twice than what we normally use, usually for numerous weeks. Also, lifestyle changes. Not eating 3 hours before going to bed, raising the head of the bed, avoiding certain foods like alcohol, caffeine, that may in fact make GERD worse.

[00:24:28]

          Chronic Cough: >8 Wk With Cough

Now let us say we go through all of this and we find out that the patient may in fact have asthma. We treat the asthma but the patient still coughs. What that would classify under is what we would call refractory chronic cough.

Then if we do this all evaluation, we try empiric treatments. Nothing is found as far as the cause of the cough. We would call that unexplained chronic cough. Now what we are seeing happening in the literature now is really putting these 2 terms together now and under the umbrella of refractory chronic cough. As we have already heard from Mike, and again, it occurs more common in women than in men, 2 to 3 times higher and again peaks in the fifth and sixth decades of life.

[00:25:15]

          What’s Next? What If the Patient Has Refractory Cough?

What do we do now that we have made this diagnosis by exclusion of refractory chronic cough? Well, some of the things we can do is refer this patient to a speech and language pathologist that has training with patients with chronic cough. There are things that they can help them, different exercises that help decrease that urge to cough, teach them about laryngeal hygiene.

There are studies to show that can definitely help decrease the cough frequency and severity in these patients. Unfortunately, at this time we do not have any FDA approved medications for the treatment of refractory chronic cough.

Now there is some that we try and you can see the list here, though, unfortunately for many patients they can't tolerate them for side effects or they may not be that efficacious. We try neuromodulators like gabapentin, pregabalin, amitriptyline. We also may try opioids such as low-dose morphine. Obviously, we have to be concerned there related to side effects and especially with long-term use dependency.

There are also some procedural therapies that may be an option in some patients including superior laryngeal nerve block, botulinum toxin injection, laryngeal fold augmentation. Again, these could be used hand in hand with some of the medications. Could refer to a specialist, like an otolaryngologist, pulmonologist, allergist, or if you have a center in your area, a chronic cough center where the patient in fact could get multidisciplinary care related to the refractory chronic cough.

[00:27:01]

Investigative Strategies Cough severity tools Additional validated tools (eg, QoL)

Now what are some investigative strategies? What are some things from the history? What are some of the tools out there as far as assessing patients related to chronic cough and especially refractory chronic cough?

[00:27:17]

          Symptoms of Cough Hypersensitivity

One that can be very helpful in the history is does the patient have cough hypersensitivity syndrome? That most of the patients we see with refractory cough have this issue. They have this problem with the urge to cough and many times they will tell you that they notice an irritation, or a tickle, even sometimes pain associated in their throat before they go into 1 of these coughing spells. They may feel globus sensation or something there that in fact tells them, "Oh, I am going to have 1 of these coughing spells occur." That can be helpful.

These patients many times have allotussia, which is a cough triggered by nontussive stimuli. In other words, in a normal patient, it would not trigger cough. If they tell you that they just taught coughing when they are talking or laughing, singing, eating, all of that are symptoms of allotussia.

Another possibility these patients can have is hypertussia where they have an increased sensitivity to stimuli at a point that in a normal patient it would not cause them to cough. Just slight exposure to cold air or drier or fumes or odors have these patients go into a severe coughing episode.

[00:28:38]

Leicester Cough Questionnaire

Now there are questionnaires that are available. This one that looks and assesses the patient's wellbeing related to their chronic cough. This is the Leicester Cough Questionnaire. This is usually used in clinical studies related to chronic cough. It is a 19-item questionnaire, 7-point Likert scale. The higher the score better.

It has 3 different domains, physical, social, and psychological. It's self-administered, takes less than 5 minutes, and it is validated and reliable. Here is the questionnaire, the 19 questions. It asks questions related to different aspects of their cough over the last 2-week period.

[00:29:23]

Punum Ladders (Cough Severity and QoL)

Now, many times this is just not practical in a clinic situation. There are other scales here that can be very helpful. This is Punum Ladders. These can be given to the patient to answer in your office setting. You can see here over on the left one measuring cough severity from zero to 10. Zero being no cough. 10 being the worst possible cough. The one over on the right looking at the patient's quality of life from no problem to worst possible problem.

There are also numerical scales that one could use 1 to 10 and also a visual analog scale, say, zero to 100, which also again can give you a score of in fact the severity and quality of life of the patient with their cough. These can be very helpful when you are managing the patient to see if the things that you are doing are in fact improving or not the patient's problem associated with their cough.

[00:30:32]

          Downloadable Patient Resource

Very important here we have a downloadable patient resource for you and you can see the URL code here, and this can be very helpful for your patients and help you in evaluating these patients. You can see the title here, what does your healthcare professional need to know about your chronic cough?

It goes into how the diagnosis is made. Goes into red flags. Goes under important aspects of how it affects quality of life. You can see the Punum Ladder here also. This can be very helpful for you when you are assessing and working up patients with chronic cough.

[00:31:12]

          Posttest 2

That leads us now to our post-test question number two. A 25-year-old man has had persistent cough for 12 weeks. He has not had a recent illness although he is being treated for seasonal allergies and GERD. In which situation would it be most appropriate to evaluate his refractory chronic cough?

A. One, if he has poor adherence to his current treatments such as allergy or GERD medications;

B. Two, if he were older - RCC is unlikely at his age;

C. Three, if his cough is triggered by nontussive stimuli such as talking;

D. The last answer, if his cough persists for three more weeks, the duration is too short right now to consider refractory chronic cough;

We will wait for the polling and see the answers.

[00:32:26]

          Posttest 2: Rationale

In fact we see that just about two thirds got the correct answer here. That in fact from his history, his cough is triggered by nontussive stimuli, which suggests again cough hypersensitivity syndrome, which goes hand in hand with refractory chronic cough. He has had the cough for 12 weeks. By definition, 8 weeks and longer is chronic cough. Again, refractory chronic cough. It may be more common in people 50 to 60 years of age, but in fact it can occur at any age.

With that, we may have a minute or so to bring Mike and Peter back in. We went over the CHEST guidelines. Is there anything else that you would like to add to that? Anything else that you do differently as far as when you are evaluating these particular patients? Mike, what is your thoughts?

Dr Benninger: Yeah, I mean everybody is different, but I think there is the cascade where you go through the very most common causes. You could do a pulmonary evaluation, PFTs, you rule out reflux, you make sure they are not on any medications, you address allergies. I think it is a really robust approach with a lot of detail and it is really when we get through those steps that we start to look at, well, are we really thinking of neurogenic cough or are we looking at really uncontrolled or recalcitrant chronic cough? I like their approach. I think it is a very well done document and a good place to start with any evaluation.

Dr Blaiss: Peter, anything to add?

Dr Dicpinigaitis: Yeah, I would just add a word of caution based on my experience and that is that running a cough center, I am oftentimes the eighth or tenth doctor these folks will see. Some of them come in telling me, "Well, doctor, you have to help me with my cough. I know it is not postnasal drip. I know it is not asthma. I know it is not reflux, but tell me what it is."

Then when I do a history, it becomes very clear that even if those top 3 that you mentioned, Michael, have been treated, often, they are not treated with the right medicine for the right duration of time at the right dose. For example, someone will tell me that they took a week of loratadine and the cough did not go away, so it can't be upper airway cough syndrome. Whereas we know that you have to use a first generation antihistamine or they used an inhaler for 1 or 2 weeks a few years ago. They were not sure if they used it right, the cough did not go away so it isn't asthma or they used famotidine for a week, the cough did not go away, so it could not be reflux.

Of course that is not true, but you really need to dig in to the details and do not let a patient tell you that something has already been eliminated from that top 4 reversible etiologies that you had mentioned, Michael.

Dr Benninger: Michael, I did agree with your comment that you said that you really have to do it for weeks. We tend to see a lot of refluxes, and a lot of postnasal drip and non-allergic rhinitis coughers. I look at 3 months of a trial before I completely exclude a particular treatment, and I do like to split them up so that they are not doing 5 different treatments at the same time.

Now if they have asthma, keep controlling your asthma, but let us look at these things individually and separate.

Dr Blaiss: All of that is great. I am going to turn it back over to Peter now.

[00:36:09]

RCC Pathophysiology

Dr Dicpinigaitis: Thank you, Michael. Let us start with a video that will review some very important cough physiology and RCC pathophysiology.

[00:36:28]

          Cough Reflex

Speaker: Before we begin a discussion of pathological cough, it is important for us to remember that cough is a very important defense mechanism. We all need to have an intact cough reflex to prevent aspiration into the lungs and to clear mucus out of the lungs.

On the most basic level, cough is a simple reflex where peripheral receptors and ion channels are stimulated in the airway to begin an afrin's vagally-mediated signal to the brainstem to induce the motor events of cough.

A variety of triggers can induce the cough reflex including chemical stimuli, mechanical, pH disturbances, thermal, but it is a vagally-induced afrin signal to the brainstem that then results in the motor events of cough.

There are multiple different receptors and ion channels in the airway that can be stimulated to induce cough. We have learned recently that 1 of the most important of which is the P2X3 ion channel that is ubiquitous in the body including the airway.

When there is an increase of extracellular ATP in the airway that can happen from inflammation or other airway injury, that increased ATP then stimulates the P2X3 receptor to begin the vagally-mediated signal to the brainstem to induce cough. As we know, the definition of chronic cough is simply a cough that has been present for more than 8 weeks.

Refractory chronic cough refers to a chronic cough that has been treated with appropriate empiric therapeutic trials against the most common etiologies of chronic cough, those being upper airway cough syndrome, asthma, and reflux. When that cough does not respond to appropriate treatment trials of these underlying etiologies, then and only then can we refer to that cough as refractory chronic cough.

Our current understanding of why patients have refractory chronic cough is due to having a hypersensitive cough reflex and we term that condition the cough hypersensitivity syndrome.

Peripheral receptors and ion channels in the airway are hypersensitive, and are stimulated by triggers that would not necessarily stimulate cough in other people. When the afrin signal then is stimulated centrally to the brainstem to induce cough and additional contributed to the cough, maybe a centrally decreased inhibition of cough. There is a peripheral hypersensitivity and a decrease in central nervous system inhibition of cough that may be contributing to the refractory chronic cough in our patients.

Clearly refractory chronic cough is a complex condition and it is probably a heterogeneous condition where different patients may have their cough induced by stimulation of different receptors and ion channels. Thankfully, in the last decade we have learned a lot about the mechanism of cough and about the relevant receptors in the cough reflex. That has allowed identification of antagonists to these various receptors to develop molecules that hopefully will eventually become cough medications.

[00:39:41]

          Pathophysiology: Cough Hypersensitivity Syndrome

Dr Dicpinigaitis: Great. That is a really nice framework for us to talk about pathophysiology. As was already mentioned, the cough hypersensitive syndrome, we introduced this concept back in 2014 to help us understand why is it that our refractory chronic coughers are coughing from triggers that do not make the rest of us cough, like cold air, strong smells, laughing, singing, talking.

The definition used in the European Respiratory Society Task Force guidelines is that cough hypersensitive syndrome is a clinical syndrome characterized by troublesome coughing, triggered by low levels of thermal, mechanical, or chemical exposure. We now understand that there is a peripheral but also a central component to this hypersensitive cough reflex that makes these patients with RCC so difficult to treat.

We talk a lot about drug therapy for chronic cough, but it is also important to understand that non-pharmacological therapies can be very useful in expert hands. We now know that our speech language pathologists can be very useful in terms of being an adjunct to pharmacological therapy for refractory chronic cough by teaching folks things like avoiding laryngeal trauma, breathing exercises, et cetera.

Unfortunately, there are still very few SLPs available who are interested in an expert in chronic cough, but they can be very, very helpful.

[00:41:16]

          Treatable Traits, Cough Hypersensitivity, and Refractory Chronic Cough

The cough hypersensitive syndrome is characterized by increased cough reflex sensitivity. That makes it even more important for us when we have a patient with RCC or whom we are evaluating for RCC to make sure that we have eliminated as much as possible other contributors to this hypersensitive cough reflex.

As was already reviewed by Michael, we want to make sure that we have treated other underlying causes that can be maybe not completely responsible for the cough, but contributors. Upper airway cough syndrome, eosinophilic airway disease reflux, but also ACE inhibitors, cigarette smoking, sleep apnea, other issues. We want to make sure that we clear the deck, all of these potential additional exacerbators of RCC.

[00:42:14]

          Model for Cough Hypersensitivity

It is interesting, what is the trigger for RCC? Oftentimes, when we think of a cough, it usually comes with an acute upper respiratory tract infection or common cold. We all cough when we have a cold, but thankfully in the vast, vast majority of us that cough lasts maybe 3, 4, 5 days. When the cold symptoms go away, so does the cough.

In a subgroup of patients, that cold comes and goes, but the cough comes and stays. The concept is that the viral infection is an initial trigger that when on top of a substrate of 1 of these underlying things or a hypersensitive cough reflex that then leads to a chronic cough. It is very interesting, and I will ask you to do this when next time you see a patient who has had a chronic cough for 5 years, 8 years, 10 years. Ask them, "Did your chronic cough start at a time when you had a bad cold or a flu-like illness?" They will think back and they will say, "No, it was a bad cold. The colds went away and I have had this dry persistent cough every single day for the last 5 or 8 years."

It seems like a viral infection can be a common trigger of what will eventually go on to be a chronic cough that can last months, years, or decades.

[00:43:37]

          Cough Reflex Arc

Again, as was mentioned, cough can be thought of as a simple reflex arc in the sense that there is a peripheral trigger in the airway that then starts a vagus nerve mediated afrin signal to the brainstem to induce the motor events of cough. What isn't simple is that as we saw, there are many different receptors ion channels that could be the initial trigger point for the induction of that afrin signal, but it is not just the brainstem. We have learned more recently that these upper brain is involved too. We now know that there are inhibitory pathways in the brain to suppress cough.

Interestingly, in our patients with RCC, these inhibitory pathways are decreased. We have less inhibition centrally while we have that hypersensitive cough reflex peripherally shooting up cough inducing signals.

The other thing we have appreciated recently is the concept of urge to cough, which is also cerebrally mediated. Oftentimes patients will tell me that the urge to cough that what could be a continuous all day sensation of a tickle or a scratch or a phlegmy feeling in the throat. Oftentimes the patient says that they find that more troublesome than the cough itself, and in fact, the cough can be a relief for a minute or 2 of that urge to cough sensation. The urge to cough is also a very important part of the chronic cough syndrome that bothers our patients, and I would recommend that you ask your patients about that as well.

[00:45:18]

          Cough Hypersensitivity Treatment Modalities

In terms of treating our patients understanding this hypersensitization of the cough reflux. Of course, we want to avoid the triggers that have been mentioned. Viral infection we try to avoid as best we can. Cold, dry air, smoke, strong smells, odors, laughing, singing, talking, things that patients know are triggers of course should be avoided.

We have learned about many relevance receptors and ion channels that initiate the cough reflex. Once we identified those receptors, we were able to find antagonists or agonists to those and those are in the pipeline as potential medications. We will speak in a moment, but unfortunately right now in 2025 in the United States, we do not have any approved medications for refractory chronic cough.

What we tend to use are, as Michael had mentioned, the so-called neuromodulators of amitriptyline, gabapentin, and pregabalin. These can also be useful for the urge to cough that patients complain about. There are also non-pharmacological interventions such as a superior laryngeal nerve blocks that Dr Benninger and his colleagues are involved in.

[00:46:44]

          Therapies in Development for Cough (2023)

Thankfully, we have learned so much about the mechanism of cough, the relevant receptors, and that has led directly into this list of molecules that are currently in the pipeline being evaluated as potential cough drugs.

By far the furthest along are the P2X3 antagonists. In fact, gefapixant has already completed phase III studies and has in fact been approved for use by the European Medicines Agency and in Japan, but has been declined by the FDA twice. Hot on its tail is camlipixant, the second P2X3 antagonist that had a positive phase IIB study and is currently in phase III studies.

You see several other very interesting molecules are currently in phase II, and hopefully these will also prove to be useful medications, but they are a little further behind the others.

[00:47:43]

          Rationale for P2X3 Antagonists in RCC

As I mentioned, the P2X3 antagonist by far the furthest along in clinical trials, the P stands for purinergic and the P2X3 receptors are ubiquitous in sensory nerves in the body including the airway. They exist in 2 forms. There is a P2X3 homotrimer, which is responsible for cough.

Interestingly, there is a P2X23 heterotrimer, which is involved in a sense of taste, and we will talk in a moment why that is relevant. In situations where there is airway inflammation or airway damage, there is an increase in ATP in the airway and that increased ATP then triggers these P2X3 receptors to begin that vagal nerve-mediated efferent signal through the brainstem to induce cough.

Now if we give inhaled ATP to healthy volunteers, some will cough at a high enough concentration, but in patients with RCC, they will cough to ATP at a much lower concentration making us believe that the ATP P2X3 receptor relationship is relevant to the induction of cough.

[00:49:02]

          Gefapixant in RCC: Phase 3 RCTs (COUGH-1, COUGH-2)

Gefapixant, as I mentioned, has already completed 2 phase III studies. The results of those studies were published in The Lancet in an article in 2022. Based on those positive data, the drug is approved in Europe and Japan. In this particular study, there was a very, very large placebo effect. Despite the large placebo effect, the larger of the 2 doses of gefapixant studied, which was 45 mg BID was still statistically significantly more effective than was placebo.

These are safe drugs. However, there was a high percentage of some perception of a taste alteration with gefapixant because of, as I mentioned, the P2X3 heterotrimer, which is also antagonized with this drug leads to in many patients a perception of something disrupting the taste.

[00:49:58]

          Camlipixant in RCC: Phase IIb RCT (SOOTHE)

Now, camlipixant is the newer P2X3 antagonist. These are the results of a positive phase IIb randomized control trial named SOOTHE. Based on the positive results of SOOTHE that this drug is now currently in phase III. This study showed a positive effect of the 2 larger doses of the drug, 50 and 200 mg. 50 mg and 12.5 mg are currently being looked at in the phase III studies.

Now, camlipixant is a much more specific molecule for the P2X3 homotrimer, and therefore because it is more specific for that, there was much less of a taste alteration appreciated with camlipixant by patients in fact, well under 10% because of this higher specificity.

[00:50:51]

          Posttest 3

Let us go to our post-test question three. A role for P2X3 receptors in the pathophysiology of RCC is suggested by:

A. Gabapentin-mediated reduction in cough frequency in patients with RCC;

B. Greater sensitivity to ATP cough induction in people with vs those without chronic cough;

C. Inability of ATP to change cough frequency in healthy individuals;

D. Receptor expression restricted to efferent motor neurons;

I see there has been an alteration since the pretest that yes, in fact cough induction by ATP is more common in those with underlying chronic cough.

Very good. Michael, we desperately need drugs for RCC because as I mentioned the United States we do not have any approved drugs yet, although thankfully we have a rich pipeline. How would the appearance of a new medication for RCC fit into your practice management?

Dr Blaiss: Yeah, I think it would be absolutely wonderful because again, what we are having to use right now, the neuromodulators, which again have not been that efficacious or patients can't tolerate, and obviously we do not want to use opioids. Having something that is safe and effective that specifically targets refractory chronic cough would be wonderful for the patient population.

Hopefully, in the near future we will have 1 or hopefully several of these products available because 1 may not be enough. Again, there probably multiple as we know receptors there. Therefore, hopefully over time having a different class of drugs that block different receptors will allow more and more patients to be under control for their refractory chronic cough.

Dr Dicpinigaitis: Yeah, you make a good point because undoubtedly the RCC patients in my mind are heterogeneous because there is so many different receptors that can trigger that initial efferent signal that you can certainly imagine that some RCC patients will have their cough mechanism through one vs another.

Mike, how about from your ENT perspective?

Dr Benninger: We tend to get involved in unexplained chronic cough and refractory chronic cough either very early with the treatment of allergies and reflux or very, very late when people have already failed other treatments or neuromodulators. Or our pulmonologists for example, send older patients that they worry about the side effect profile with neuromodulators to us for nerve blocks.

We know that about 50% of people who have that will respond to nerve blocks, but it may not be permanent and there is some tachyphylaxis with that. So by the time we get done, they have tried everything. We tend to be the people that they are saying, "You got to find me something." There is so many patients that I have that they have failed little bits across the way, but once they have tried everything, even if we only get a 50% response, that is another 50% of patients that are going to be better. I think there is a great need for having 1 more step in our process and our arsenal

Dr Dicpinigaitis: Let us hope when these drugs are available, patients will get them before they get to see 1 of the 3 of us.

With that, Mike, let me pass it back over to you.

[00:55:16]
          Summary

Dr Benninger: Quick summary. Chronic cough is cough lasting for greater than 8 weeks. Chronic cough with no diagnosable cause is unexplained chronic cough and chronic cough that does not resolve a treatment of various potential underlying causes is refractory chronic cough. There are current no FDA approved treatments for UCC or RCC.

RCC can last for many years and has a huge impact on people's lives. Another term for that is cough hypersensitivity syndrome that Peter discussed, and I think better understanding of the process and contributions of cough hypersensitivity syndrome is hopefully leading to the development of specific therapies and furthest along the path is the P2X3 antagonists.

[00:56:13]

Questions & Answers

What I am going to do is I am going to go through the questions that have come in and I am going to split them up between the 3 of us. I do not know that we want to talk about CANVAS syndrome because it is relatively rare. Do either of you want to mention anything with CANVAS syndrome?

Dr Dicpinigaitis: I will mention it quickly because it is rare, but CANVAS means Cerebellar Ataxia Neuropathy Vestibular Areflexia Syndrome. It is a neurological syndrome. It is RFC1 genetic. What is fascinating about it is that the second symptom is usually ataxia, but these CANVAS people have been looked at and in a large series of over a hundred canvas patients, over 60% of them had chronic cough.

The chronic cough can predate the first neurological symptom by years or decades. We may be looking at RCC patients today who 10 years from now might be diagnosed with CANVAS. It is fascinating, but I think I do not want to spend too much of the remaining of our time on that.

Dr Benninger: Peter, do you want to mention what is the mechanism of cough with ACE inhibitors?

Dr Dicpinigaitis: Two of the most potent cough inducing substances are bradykinin and substance P. The enzyme ACE metabolizes bradykinin and substance P. When we take an ACE inhibitor, we then get an increased amount of bradykinin and substance P and prostaglandins for that matter in the airway, and that is why ACE inhibitors cause cough.

Dr Benninger: I will take a gander at the next one. How has post-COVID infections affected treatment of chronic cough? I think the main thing that we see with post-COVID is it may be the inciting episode. Michael talked about these inciting episodes where you may have had a virus or cold.

I think the bigger issue is that people are much more attuned to cough. I had a patient that used to cough all the time in church and people just knew she was in church because she was coughing. Now people will not sit near her in church. I think it has focused us on the social and personal relationship issues related to chronic cough.

Mike, there is 2 in a row here. First generation antihistamines are not good for our brains. Can you speak to first generation, second generation antihistamine treatment for cough?

Dr Blaiss: I agree. This is my exception to the rule when I am teaching students and fellows. This is the condition that the only one that I use a first generation antihistamine for. The reason is, is the second generations do not work in this condition. Now if they have allergic rhinitis, then yes, but if we are talking about a true postnasal drip syndrome that is not due to allergies, then one needs a first generation antihistamine with its anticholinergic activity to help dry up that mucus that in fact may in fact be what is in fact triggering their particular cough.

As far as which first generation agent I start with? I usually start with chlorphenamine and usually start at bedtime. Because again, it can cause sedation and then titrate it up as needed. Really I usually start with something like, usually the first line I use is chlorphenamine.

Dr Benninger: The other thing is ipratropium bromide may also be effective in some of those patients in reducing the amount of postnasal drainage, although it can thicken the mucus, which may actually make it worse.

Do people actually have access to the questions? But there is a long comment basically about silent reflux and there is no real way to make the diagnosis or LPR; laryngopharyngeal reflux. pH probe and manometry can be effective in helping make the diagnosis. I will tell you that now a trial of therapy is probably the best way to go. What I do is put them on a low acid diet to anti-reflux positioning, elevating the head of the bed if they can. I usually put them on a twice daily proton pump inhibitor and a nighttime H2 blocker and use 1 of the barrier blockers for rescue. If they fail that even if we do not have a specific diagnosis, they probably do not have reflux. I think particularly people are looking at pepsin and non-acid reflux and therefore a GI evaluation is clearly indicated in these patients and our cough team is not on pulmonary, allergy, EMT, speech, but also GI.

I think an aggressive treatment. The barrier blockers should be fairly effective if people stay above 30 degrees with non-acid reflux. Do you anticipate clinicians using these upcoming new treatments acutely, short-term, or long-term? Peter, do you want to answer that?

Dr Dicpinigaitis: The 2 newest ones along gefapixant, as I said, is already approved. Camlipixant phase III studies will finish next year. With the P2X3s, we know from phase II studies that if you are going to have an effect on your cough, you will know by four weeks. It is not like you have to do a year of therapy to know. That is going to be helpful. The obvious question is, well, what about for that stubborn post-viral cough? It will not be labeled for such, but obviously the drugs may be effective for it, but they will be labeled specifically for RCC.

How does bronchiectasis fit into the RCC treatment realm and someone with a Chiari I malformation? That seems pretty specific. Does anybody want to address this or do you want to go on?

Dr Dicpinigaitis: I think bronchiectasis is just damaged airways and a lot of secretions irritating what could even be normal sensitivity receptors. I think it is a different issue than RCC and a neuropathic cough possibly.

Dr Benninger: Do we see an increase in bariatric patients, Michael?

Dr Blaiss: I am not aware of any data. May be Peter knows. I have not seen any data that suggests that BMI had a major role here as far as a higher rate of patients with refractory chronic cough. Peter, have you seen any data?

Dr Dicpinigaitis: No data other than simply to say that those folks would be more likely to have acid reflux and that should be then looked at. Weight itself, I am not aware of any studies.

Dr Benninger: The 1 thing that is becoming more and more apparent is that some of the new medications because it delays gastric emptying, we are seeing a dramatic increase in reflux in those patients. We will end with 1 last question. When would gabapentin or pregabalin be used for RCC? Either of you, Michael or Peter, please.

Dr Blaiss: Once I ruled out the major causes that we talked about, the big 4 there and empiric treatment has not helped any of those patients, then that is when I would usually start with gabapentin. I think it is important that you start with a low dose and slowly titrate up, so have a higher likelihood for patients to tolerate the medication.