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Dr. Purvi Parikh: Welcome to this special edition of Allergy Talk from the American College of Allergy, Asthma, and Immunology. I am Dr. Purvi Parikh and this is the first in a three part series on cough. Understanding the Cough Reflex. Cough remains one of the most common symptoms for which patients seek medical care. A new paradigm has emerged of patients with chronic cough that do not respond to asthma, rhinitis, and or a gastro esophageal reflux therapy. We're here to help allergists understand the different therapeutic agents available now and in the future and their mechanisms of action in all stages of cough. Joining me are Dr. Kevin Murphy, the Director of Clinical Research at Boys Town National Research Hospital in Omaha, Nebraska. He completed a fellowship in allergy, asthma, immunology and pediatric pulmonary at National Jewish Hospital and he is a spokesperson for the American College of Allergy, Asthma and Immunology.

And Dr. Mandel Sher, Clinical Professor of Medicine and Pediatrics at Morsani College of Medicine at University of South Florida in the Division of Allergy and Immunology. Dr. Sher Is the Head of the Center for Cough in Largo, Florida with large chronic cough population and engaged in clinical investigation in promising and novel cough suppressant controllers. He is a speaker on local, regional, and national level on diagnosis and treatment of chronic cough and is also a spokesperson for the American College of Allergy, Asthma, and Immunology. Welcome to the show Doctors, so let's get started. Mandel, would you describe for our audience the cough reflex and comment on why it is important for physicians to understand the cough reflex?

Dr. Sher: Thank you, Purvi. The ability to cough is absolutely critical to our survival. We need to cough out aspirate and materials such as food or acid and we have to be able to clear mucus deep from our lungs, be it from infection or inflammation. This cough reflex is mediated by a rapidly transmitted vehicle nerve fibers and we call these Alpha Delta and they're located throughout the respiratory track. There's a sensory signal that is sent to our midbrain which is immediately responsive with the resultant motor signal resulting in a cough. Of importance, this cough reflex is hard to suppress and even occurs when asleep or being unconscious. Now there's a second type of cough response. Some people call it a cough reflex, but this is actually a cough response. And it's mediated by nociceptive type C nerve fibers located in our respiratory track, in our esophagus, and probably up in our upper airway. This referred to as the chemo sensory response.

And it's triggered off by irritants and inflammation, particularly that viral upper respiratory infections. And instead of an immediate response that you see with that true cough response, this leads to a tickle or an urge in the back of their throat. And this signal is transmitted not only to the midbrain, similar to the cough reflux, but it's up to our upper brains, our cortex. And in contrast to the true cough reflux, this cough works by a response of sensory input of this urge or a tickle. And this tickle cough tends to go away during sleep and is not seen in an unconscious state. This irritative cough response is mediated by multiple receptors and neuronal pathways and there's many promising pathways that are being investigated that mediate this important urge to cough response and one of them is P2X3 triggered off by ATP, another is neurokinin 1 triggered, off by substance P, and TRIP V1, which is trigger off by capsaicin. What is really interesting here that these are the same pathways that mediate itch and low grade pain, so there's lot of similarities between chronic pain, chronic itch, and chronic cough, all of which are really important to our listeners. Allergists.

Host: Okay. Thank you very much. Kevin. Are there any aspects of the cough reflex that are important in children specifically with chronic cough?

Dr. Murphy: Yes, there are some what I believe to be very important differences between adults and children. Again, it's important to emphasize that cough is a protective reflux that enhances mucociliary function and clears excessive secretion, and airway debris from the respiratory tract. The cough reflux has, as we've heard, vagal input and then cortical modulation with motor offeree activity involving the respiratory muscles. In children, there is a developmental process and a maturation of the offeree plugs. In early life cough is related to primitive reflexes that are laryngeal chemo reflex is that over time undergo significant maturation. So when we think about children, especially younger children, the cough reflex can be more sensitive than adults to environmental exposures, infection and certain irritants. Thus children cough differently than adults in terms of their duration, the presentation, and especially the underlying causes for chronic cough.

Dr. Sher: You know, Kevin, that's a really interesting that you bring up this maturational aspect, particularly with the irritative or increase urge to cough because as we'll talk about in these sessions, cough hypersensitivity as an etiology for chronic cough is really unusual in children. And I think part of that explanation, the fact that they have not developed that urge or chemo sensory cough to the point of adults.

Dr. Murphy: I can't agree with you more. And I think as we discuss this further, it, it really separates children from adults, especially as we think about the different etiologies for chronic cough.

Host: Ah, wonderful. So, Mandel in your practice, you know, how do you approach the discussion of cough reflex with your patients?

Dr. Sher: Well, that's a really important question and it's really important as you talk to these chronic coughers who it's a new concept for them. So I try to demonstrate that granularly. And the first one is differentiating that true cough reflux. So I say, what happens if you put your finger on a hot stove? And I immediately put my hand back to over my head and they see that, they realized that they touched the hot stove after the fact that their hand has been thrust away. So similarly with a true cough reflex, you don't think about it. It just happens and you realize that it happened after it happened. Now when it comes to the increase urge to cough or that chemo sensory cough, I go, what happens if my wrist is itching? And then I go over and I scratch my itch on my wrist and they go, wow, that's something you have to do purposefully. So they almost universally have this urge to cough or itch in their lower throat. And I say, what do you do with your itch and your lower throat? And they say, well, I scratch it, I cough. So this concept of true cough reflux, which is a survival technique versus this response to a noxious stimuli, which is either scratching an itch or coughing and getting rid of that sensation in your throat is how this is explained and usually it works pretty well.

Host: Kevin, how do you approach that discussion of cough reflex with your patients?

Dr. Murphy: Well, let me first say that I thought Mandel's example of what you do when you touch a hot stove was terrific. And I think that particularly families in children very much can relate to that. I also think it's important in pediatric patients to talk to families about what is considered normal or expected cough. And I share with families that normal healthy school aged children will typically experience 10 or 11 brief coughing episodes a day. However, these normal coughing episodes are often a trigger, many parental concerns. And in children, as Mandel previously mentioned, one aspect to the cough reflux that is common and that I talk to families about is a post-infectious cough, which is the result of a heightened cough reflex sensitivity. Important though in children, post-infectious cough is common. However, in children with chronic cough, it's been shown that less than 5% of cough persisting over eight weeks, except for pertussis in children, is thought to be posed infectious.

Host: Thank you. I couldn't agree more. I know a lot of what we do is these discussions and managing expectations because often patients come in with a certain preconceived notion of what is triggering their cough. And very often that may not be the case. So, you know, moving forward. Mandel, I know you had briefly touched on cough hypersensitivity and the difference between adults and children. Can you discuss that condition, expand on it a bit more?

Dr. Sher: Surely, cough hypersensitivity is actually a fairly novel term over the last years and it really refers to an increased urge to cough response either as the sole reason for why the person has their chronic cough or it can be associated with other triggers of cough, be it acid, non acid, GERD, upper lower airway infection, or inflammation, as well as the lower airway process. And while the mechanisms of cough hypersensitivity are not well known, there clearly is a hyperreactivity or a hypersensitivity of the sensory input pathways but also as the motor or efferent out pathways. And because of this nociceptive type C receptor, chemo sensory, increased urge to cough pathway, there's clearly a higher cortical involvement, which is in contrast to the true cough reflex. So we have this central sensitization.

And as you, I say this, it's also could be the same explanation for chronic [inaudible 11:44] or chronic pain. And so the literature is very similar and actually the medications that are being tried for cougher being used to niche and using and pain. So there'll be, you know, this trilogy of processes that benchmark from each other. So the chronic cougher in these situations has an increased response to typical triggers, particularly that the viral upper respiratory infection, which as Kevin's referred to in children and Purvi has, which I believe is a neurogenic irritability. That cough that we see in colds is after the mucus. It's the mucus is gone. You're not clearing mucus, but you actually, you probably get cell injury and nerve injury that's causing this sensitivity. But in cough hypersensitivity syndromes and states actually normally harmless processes will activate the cough and the most common ones talking. We see that in these chronic coughers talking, on the phone, being a school teacher, will trigger off their cough. And other typically non noxious events such as smells or change in temperature or a draft will induce this cough. And as I've mentioned before, this is mediated by multiple different nociceptive type z pathways and what's being explored is which ones are more relevant. And again, that's, it's leading to the development of new antitussives, which I like to call cough Neuromodulators.

Host: Great. That's very helpful. Kevin, can you discuss the clinical manifestations of cough and the burden of disease that you see in your patients specifically?

Dr. Murphy: Yes, I, I think, as clinicians it's very important to have an understanding in children about the clinical manifestations of cough, and I find it helpful to ask the family five questions about their child's cough. First, how long is the child cough? Most guidelines define cough as acute lesson, three weeks subacute, three to eight weeks and chronic greater than eight weeks. And most acute and subacute cough and children, as we've mentioned, are associated with viral upper respiratory tract infection and do not require specific diagnostic evaluation. The second question, which is very key for children is the character of the cough. The character or quality of chronic cough in adults has been shown to be not helpful in predicting specific etiology for the cough. And the American College of Chest Physician guidelines recommend that often the character of the cough not be used in determining an etiology in adults. In contrast, the character or quality of coffin children is traditionally recognizable, age specific, and very helpful in determining a specific etiology.

What has really become an important question to ask because it helps in regard to the etiology of cough is whether the cough is wet or dry. The descriptor, wet or moist cough may be used interchangeably with productive cough. Even though young children rarely expectorate despite excessive secretions. A very good recent review of wet cough in children, those children without cystic fibrosis, found that the majority of children with wet cough had an endobronchial bacterial infection and chronic wet cough is very rare in children with uncomplicated asthma, however, does occur in children with sinusitis and may also be very responsive to antibiotic therapy. We often ask about nocturnal cough and it's been often cited that that's a hallmark of asthma. However, most objective studies have not confirmed this finding, and parental reporting of nocturnal cough is thought to be unreliable compared to other objective measures that we can perform in regard to pulmonary function assessment, exhaled nitric oxide in making the diagnosis of asthma.

The absence of cough especially at night is helpful as habit cough most characteristically ceases at night. And finally the age of the child plays an important role in regard to the etiology of chronic cough. Keeping in mind that younger children demonstrate different causes of chronic cough compared to those with predominantly older children and adolescents. It's especially important to remember that infants and younger children, are more likely to have an anatomical abnormality of the upper or lower aspiratory track, and possible foreign body aspiration compared to an older child, adolescent or adult. One thing that I find and I'll be interested in Mandel's thought about this, is that chronic cough, regardless of the age, can intensely interfere and be a burden for patients and families in regard to quality of life interfering with sleep, missing school and work. Thus, it's not surprising that parents are often anxious and very concerned about their child's cough and often seek medical advice and treatment for a child who has had persisting cough.

Dr. Sher: Well, Kevin the burden that you see in children and their parents is different but very intense as we look into adults with chronic cough, as I've mentioned before, it's 75% of their chronic coughers tend to be women and they tend to be in their 40s, 50s, 60s and 70s. And as they present to our clinic and cough doctors clinics, and it's been documented in literature, there's a tremendous amount of dysfunction, psychologically, socially and physically. The rate of urinary incontinence is high, very high rate of anxiety and depression, feeling very isolated socially and affecting workplace and their personal relationships. So it's now becoming appreciated that this is a more than just a nuisance, but as a very significant problem. And the problem right now is that there's this unmet need of these patients, which is we don't have good cough medications. We don't have good antitussives. The medications at work have significant side effects. Primarily the opiates and we'll talk more about that in upcoming sessions. And the medications that we do have don't work very well. The last two medications approved by the FDA for cough was in 1958. So what I think is going to be exciting, particularly as we discuss in upcoming sessions, is the development of some candidate new novel antitussive neuromodulators for cough.

Host: Thank you. And I couldn't agree more. It is quite burdensome in all of my patients as well really affects their quality of life. And the point that you made regarding the parents and how unreliable their history may be is especially important because, you know, in the pediatric population, we do rely on the parents for most of the history, especially if the child is very, very young. So even I learned something on that point regarding the history of the nocturnal cough. So thank you. And I'm excited to hear about these new treatment options that are on the horizon. That being said, Mandel, how do you describe the unmet needs of your cough patients?

Dr. Sher: Well, it's as I mentioned before, it's the lack of therapy that we have. These medications again, either have adverse side effects or they just don't work very well. And while we'll discuss some lifestyle approaches in the upcoming sessions of how we can help people with acute and particularly chronic cough, the biggest need is getting new cough medications to our patients.

Host: All right, well thank you to our guests and to all the listeners that concludes part one of our three part series on cough from the American College of Allergy, Asthma, and Immunology. Please be sure to join us for future episodes on diagnosis and treatment options and cough. For other interesting episodes from Allergy Talk, please visit college.acaai.org/Allergytalk. To receive CME credit for this or other eligible Allergy Talk podcast, please visit education.acaai.org/allergytalk. I am Purvi Parikh for the American College of Allergy, Asthma and Immunology.