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An Allergist on Chronic Cough
Conversations in Chronic Cough: An Allergist’s Perspective

Released: May 28, 2025

Michael S. Blaiss
Michael S. Blaiss, MD
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Activity

Listen as Michael S. Blaiss, MD provides case-based perspectives on chronic cough recognition, burden, management, and pathophysiology and describes the evolving treatment landscape for refractory chronic cough.

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Hello. And what I want to do for you today is give you the allergist perspective as we look at patients with chronic cough. We need to start with that question of why do we cough?

Well, it is a very important protective mechanism. It is important as far as being able to clean out the airways from irritants, smoke, mucus. Unfortunately, all of us know, as allergists, we see patients on a daily basis that come to us with a cough that in fact has become pathologic.

Cough: Definition

How do we define cough? If one goes through the literature, there have been many different ways, but probably the major way is cough duration. We can divide cough into three groups by duration. One is acute cough, with the most common cause being upper respiratory tract infection. These are by definition a cough that is three weeks or less.

Next would be a subacute cough from three to eight weeks, with the most common being that post-viral cough, though you can see it with pertussis and mycoplasma.

But what we are going to talk about today, in fact, is chronic cough. These are patients that come to us that have been having cough for greater than eight weeks.

Chronic Cough: Epidemiology

What is the epidemiology of chronic cough? In fact, it is extremely common. In fact, worldwide numbers suggest somewhere between 10% to 12% of the population. We know that chronic cough can occur at any age, but it is more likely in people over the age of 40.

When we look at chronic cough itself, it does have a slight female predominance. Commonly, these patients in fact have a history of smoking. But a very important subset here is refractory chronic cough. These are patients that have a chronic cough that we find no diagnosable cause or the potential underlying causes of the cough had been treated. But unfortunately the cough still persist.

As mentioned, this is a subset of chronic cough. Some studies suggest that up to 40% of patients with chronic cough have refractory chronic cough. We know that it is much more common in women than in men. In fact, three to one. The typical ages that we see are usually patients between the ages of 50 and 70. It is thought to be driven primarily by a cough reflex hypersensitivity.

Cough Hypersensitivity

What are the symptoms of a cough hypersensitivity?

Well, one is that urge to cough. These patients tell us they get this irritation, this scratchiness, this pain in their throat or sometimes a tickle in their throat, or they feel that something is there and they get this urge to cough that they cannot stop. They may also have allotussia. An allotussia is a cough triggered by non-tussive stimuli. Things like talking, laughing, singing, eating.

These patients commonly have hypertussia, which is an increased sensitivity to a stimulant. Things like cold air, dry air, odor, dust. Again, in levels that do not make the normal person have a cough spasm.

Evaluation of Chronic Cough

How do we evaluate patients that in fact come to us with chronic cough?

There have been many guidelines that have been published over the years. But the one we tend to use the most was developed by Cough Expert Panel from the American College of Chest Physicians. This was published in their Journal of Chest on classification of cough is a symptom in adults and management algorithms.

They talk about the initial assessment of patients with chronic cough. Obviously to begin with the history:

  • We need the length of time of the cough;
  • What type of triggers are causing the cough to occur? Is it from different environmental exposures or occupational exposures;
  • What about the family history, especially allergies and asthma;
  • Smoking history is obviously very important;
  • What type of previous evaluations and treatments have these patients had;
  • We need to know all their medications, prescription, over-the-counter, herbal treatments; and very importantly,
  • Are they on any medications that could cause chronic cough such as ACE inhibitors.

Patient Case

Let us look at a patient. Joan is a 51-year-old female with a cough. She has been having this cough present for about the last four years. She tells us that it started with an upper respiratory tract infection. She tells me that her cough is getting worse and she has these uncontrollable bouts. She has been seen by her primary care physician who has tried different over-the-counter cough medications and even tried benzonatate with a prescription, but that did not help either.

Chest x-ray two years ago was, in fact, completely normal, and she tells me otherwise she is in good health. There has been no weight loss recently with this condition.

She tells me the cough is non-productive and she notices a tickle in her throat before coughing. She tells me that getting round any mild odor in fact causes her to cough. Even laughing causes her to cough. One of the things that really bothers her is that sometimes when she is having a bad cough spasm, she has bladder leaks associated with it, and therefore she is very embarrassed to go out in the public because she does not know when this would happen again.

The other thing that bothers her, she is afraid she has a serious disease. No one is found in fact, the cause for her problem. On past medical history, it is really unremarkable. She has had no use of ACE inhibitors, family history, father with allergic rhinitis. She is a non-smoker and she has been an accountant for the last 25 years.

Her physical exam was unremarkable. Her nose showed some mild, swollen turbinates without drainage. Her throat had a slight post-nasal drip. Chest was clear. Heart sounds were normal, and her skin, in fact, was clear.

Now, if we look at the CHEST guidelines, it tells us very importantly to look for red flags. These are conditions that could be associated with life-threatening causes that can lead to chronic cough, things like hemoptysis or a smoker older than 45 years of age with a new cough, or a patient with prominent dyspnea, especially at rest or at night that could be congestive heart failure, or systemic symptoms like fever or weight loss which could be related to a malignancy, or recurrent pneumonia, or an abnormal respiratory exam and/or an abnormal chest x-ray that coincides with the duration of cough. But in this case, in fact, Joan does not show any of these.

Where do we go from there in our patient?

Well, in most cases of chronic cough, we have a patient like Joan that is immunocompetent. She does not smoke, has a normal chest x-ray. There are four conditions that we have to evaluate. One is upper airway cough syndrome, which we used to call post-nasal drip syndrome related to sinus and nasal problems, both allergic and/or non-allergic asthma, non-asthmatic eosinophilic bronchitis, and gastroesophageal reflux disease.

First, in Joan, we have assessed her asthma non-asthmatic eosinophilic bronchitis. Her spirometry was normal with no response to a bronchodilator. We did bronchial provocation testing and, in fact, she showed mild reactivity. Her exhaled nitric oxide was normal at 10 parts per billion.

We did an empiric treatment with oral corticosteroids, a seven-day burst. In fact she showed some mild improvement, but unfortunately her cough has continued to persist. An evaluation of upper airway cough syndrome. I did allergy tests, which were all negative. Her CT of her sinuses was normal. I did an eight-week trial of a first-generation antihistamine and she showed no improvement. The reason for a first-generation antihistamine is because they have anticholinergic activity, which could help dry up a postnasal drip. We would not use a second-generation antihistamine here because they do not have anticholinergic activity.

Then, as far as GERD, I placed her on PPIs and we did lifestyle diet change. We had her raise her head of her bed and not eat three hours before going to bed. We did this for two months. There was no improvement in her cough. For that reason I decided to refer her to a GI specialist for a full reflux workup, which in fact turned out to be negative.

What are we dealing here with Joan? We have a cough that continued despite treatment for underlying asthma, at least from her positive bronchoprovocation test. We have ruled out all the other causes. She by definition then has refractory chronic cough.

What is next? What do we do today for a patient with refractory chronic cough?

Well, one, is we can refer to a speech and language pathologist for evaluation, ones that in fact have knowledge as far as treatment of patients with chronic cough, there are many things they can do for them. Certain types of exercises, procedures. Very important as laryngeal hygiene.

Presently, we have no FDA approved treatments for patients with refractory chronic cough, though in the literature there are some studies showing some neuromodulators may have some benefit for patients, including gabapentin, pregabalin amitriptyline. Unfortunately, many patients get no benefit, and these come with a great deal of side effects for many patients.

Also, opioids are used sometimes, including low-dose morphine. Unfortunately, we know that chronic use of opioids can lead to significant dependency. We could refer to another specialist. If we think there is something else going on in the lungs, we could send that patient to a pulmonologist, maybe to an otolaryngologist for further assessment of the upper airway.

As I did in this patient, refer to GI for a complete reflux workup. Depending upon the area you live in, you may be able to send the patient to a chronic cough center where, in fact, they would have a multidisciplinary approach as far as management of these patients.

Therapies for Cough

Now, what is exciting is that there are a lot of therapies in development for cough that hopefully in the near future we may see for our patients. There are agents that block the P2X3 receptor. There are also agents that block the sodium voltage channel, which is extremely important as it can be triggered and lead to cough. We have a TRPM8 agonist, which in fact have an effect on a receptor in the upper airway, which seems to be very important as far as stopping cough.

There is also products in development that are kappa opioid receptor agonist, mu-opioid receptor antagonist. One, in fact, just finished a phase II study that showed a significant effect in patients with refractory chronic cough. This is unlike your typical opioids because it does not in fact lead to dependency.

Very importantly are the role of P2X3 antagonist in refractory chronic health. The P2X receptors are ATP-gated ion channels. We have the P2X3 and the P2X2/3 receptors that are expressed on vagal sensory neurons, both the peripheral airway terminals and central terminals.

Now we know ATP is involved in airway disease and inflammation. It can act as a damaged signal. It is released in response to a lot of different stimuli, injury, inflammation, environmental stimuli, and it itself can drive further inflammation.

ATP in fact binds to these P2X3 receptors and can evoke cough in people with and without chronic cough. But the response in fact is greater at lower concentrations and people with chronic cough.

Gefapixant

We have had the development, in fact, of P2X3 receptor antagonist. The first product I want to mention is Gefapixant. It has finished two phase III studies and did show a significant decrease in 24-hour call frequency at both 12 weeks and 24 weeks.

Now, this product also has high binding to the P2X2/3 receptor, and this receptor is found on the vagal terminals, but is also found in fact in the taste buds and in fact leads to taste abnormalities associated with the use of this product. In fact, up to 68% of the patients had some type of taste alteration.

Now it did show acceptable safety. Nevertheless, the FDA twice refused to approve this product in the United States, though it is approved in other countries.

Camlipixant

The next product is Camlipixant, and this agent, unlike Gefapixant has minimal activity against the P2X2/3 receptor, and therefore has minimal taste alteration.

In its phase IIb study, it shows significant effect as far as a decrease in the 24-hour call frequency. Presently, this product is under phase III study, and hopefully in the very near future we will have the results with this particular product.

Conclusion

In conclusion, refractory chronic cough is a serious condition that has a major effect on the quality of life of the sufferer. An extensive workup by the allergist is needed in the patient presenting with chronic cough before one labels the patient with refractory chronic cough, as refractory chronic cough basically is a diagnosis now of exclusion.

Now the treatments are limited today for patients we see with refractory chronic cough. But no doubt the future is bright with all the different products in development.

Thank you.