FeNO to Help Guide Asthma Treatment

In this podcast, Sumita Khatri, MD, MS, and Teal Hallstrand, MD, MPH, speak about a new clinical practice guideline on fractional exhaled nitric oxide (FeNO) to help guide asthma treatment, including detailed explanations of the studies the expert panel evaluated and considered when making this recommendation.

Additional Resource:

• Khatri SB, Laccarino JM, Barochia A, et al; American Thoracic Society Assembly on Allergy, Immunology, and Inflammation. Use of fractional exhaled nitric oxide to guide the treatment of asthma: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2021;204(10):e97-e109. https://doi.org/10.1164/rccm.202109-2093st 

Sumita Khatri, MD, MS, is a professor of medicine at the Cleveland Clinic Lerner College of Medicine, director of the Asthma Center, vice-chair of the Respiratory Institute, and an adult pulmonary and ICU physician at the Cleveland Clinic in Cleveland, Ohio.

Teal Hallstrand, MD, MPH, is a professor of medicine at the University of Washington, a physician-scientist, and the director of pulmonary diagnostics at the University of Washington, Montlake in Seattle, Washington. 

TRANSCRIPTION:

Jessica Bard: Hello, everyone, and welcome to another installment of "Podcast360," your go‑to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant360 Specialty Network.

According to the Asthma and Allergy Foundation of America, an estimated 1 in 13 Americans have asthma. Doctors Sumita Khatri and Teal Hallstrand are here to speak with us about a new clinical practice guideline on fractional exhaled nitric oxide or FeNO to help guide asthma treatment.

Dr Khatri is a professor of medicine at the Cleveland Clinic Lerner College of Medicine, director of the Asthma Center, vice-chair of the Respiratory Institute, and an adult pulmonary and ICU physician at the Cleveland Clinic in Cleveland, Ohio.

Dr Teal Hallstrand is a professor of medicine at the University of Washington, a physician-scientist, and the director of Pulmonary Diagnostics at the University of Washington Montlake in Seattle, Washington.

Thank you for joining us today. Can you please give us an overview of the new clinical practice guideline?

Dr Sumita Khatri: Sure. Maybe I'll go first on this one, because I think Teal and I were both so excited about this new concept. It was unique.

We have been maybe peripherally aware of how guidelines have been set forth by ATS. They were trying something new, something a little bit more agile and rapid, so that it doesn't lose its luster by the time it's published.

Kevin Wilson reached out to us that the ATS leadership was offering three questions for us to potentially consider for exhaled nitric oxide, FeNO measurement.

We knew the timeline was quick. We were up for the challenge. We started with this very unique process of coming up with the committee, a multidisciplinary panel that we assembled with a group that was expert in clinical care, research and evidence-based methodology.

The success of this would not have happened without that collaborative expertise. I'll be honest with you, I'm a fan of that rapid turnaround. We've been waiting for guidelines quite a bit throughout our careers and the fact that this sets a new standard. We needed to get the information quickly out as evidence is always changing.

I know we were both initially contacted in March of 2019 and launched the project in May of 2020. Of course, we had that little hiccup of world affairs going on, but we still were able to manage to turn it out with minor revisions in May of 2021 and publication as you know here in November.

We're very proud of the process and the collaboration and the spirit in which it was all brought together. Teal maybe you can speak to how we chose the question.

Dr Teal Hallstrand: Sure, there was an original guideline in this area on the use of exhaled nitric oxide that was published quite a long time ago. I'm not sure that I know the exact number of years, like 10 years ago.

It's been highly cited. It gave the rationale for using exhaled nitric oxide as a measurement in asthma. It also proposed initial cut points in which you might use to make clinical decisions.

I think the main intent was to try to identify the most important single question that could be addressed, that would be most useful to clinicians to take this forward from that initial guideline, which was a very rough outline of the reason that we use exhaled nitric oxide and the cut points.

In case you're not familiar with that guideline, initial guideline suggested that people with elevated levels about 50 in adults, would be people that had uncontrolled inflammation and might benefit from intensifying their therapy. Then below 25 was low exhaled nitric oxide, suggesting that airway inflammation was well controlled.

Since that guideline was published, everyone recognizes that there's quite a bit of literature that's been developed. As Sumita was saying, I think to be agile, since these guidelines take a lot of effort as far as analysis. We decided to choose the question that was the most important.

Leadership from the American Thoracic Society proposed three potential questions. Sumita and I, we agreed to co‑chair this new guideline. I think the first thing that we did that was important is we assembled a group of people to help us with identifying these questions.

We identified experts in the field, mostly based on our own networking and familiarity with people that we thought would be good for this. Then we had a team of three methodologists who helped us with this. Once we assembled the team, we actually voted on which question was the most important.

Those three questions were essentially about the question we chose, which is should you use exhaled nitric oxide to make clinical decisions and initial evaluation of someone with asthma, not necessarily their first evaluation, but during your first initial evaluation.

The other two questions are essentially about whether or not it could be used as a diagnostic tool to decide if someone has asthma and to be used as monitoring. We had the committee vote and we chose that question as the highest priority. Once we had the committee formed, we then use the process called grade.

I don't think I should go into the exact details about the statistical methods. One of the key things about grade is it's a way to use systematic literature review.

To me, the key thing there is that, you have to pre‑specify what outcomes you're going to look at. You have to prioritize the outcomes. We also used our committee to decide which were the highest priority outcomes beforehand.

Things that we thought were high priority are in the table and the guideline. These things are things that we all know as clinicians that are very important, such as asthma exacerbations, or asthma attacks, and need for corticosteroid bursts, things that we use when we encounter people that have uncontrolled asthma, we also prioritize that.

We did with the methodologists help, which I have to say was incredible. We did a systematic review and identified the literature that would help us answer this one most important question with these priorities.

The recommendation that we made was from this very rigorous process, and was the result, not only we essentially met every few months, for quite a while to go over these things to come up with a recommendation. Sumita, do you want to comment further on that?

Dr Khatri: Actually, you did such a nice job of explaining how this all came to be. I thought it would be helpful for me to share what our goal was, which was to provide guidance to clinicians who manage adults and children who are four years of age and older.

Our audience is very much the people we're hoping are listening to this podcast, which is pulmonologist, allergist, and primary care physicians, the chronic management of asthma.

All along, as much as I love the translational research that went into the discovery of exhale nitric oxide and how it's used in clinical care, I wanted it to be practical, less esoteric, and where clinical judgment plays a significant role. We'll go into what we found as our results.

I would like to highlight for people who are interested in this guideline to look at figure two because it's the gold guidelines. We wanted it to have an assessment of whether asthma is controlled, and exacerbations are low, versus asthma exacerbations are high and use of steroids are high.

Where does that factor into the nitric oxide levels, which we weren't putting, cut points for. We assumed it was like a slide rule gradient, which allows for clinical interpretation. We felt that that was very, very important to do.

When we looked at the critical outcomes, you talked about asthma control, use of oral steroids, exacerbation rate, ER, or urgent care or hospitalizations, that's what people thought would be important.

As it comes out, we found that the outcomes where phenol was most helpful was when we were looking at use of oral corticosteroids or oral corticosteroid use rate as well as acute exacerbations. Very patient‑reported outcome related, and this is why we think that the clinician will find this to be very helpful.

Dr Hallstrand: The outcome measurements that we had pre‑specified as being the most important clinically were actually the outcomes where there was the strongest evidence. That was an important point.

Jessica: What studies and how many did the expert panel evaluate and consider when making this recommendation?

Dr Hallstrand: Right. We started broadly with two approaches. One was using a structured literature review that the methodologists helped us with. We also started looking at other studies that had done similar systematic reviews to help inform which studies that should be included.

Then, the methodologist looked at these studies individually and determine which studies were most appropriate for our question. Remarkably, that whittled it down over the selection process, just down to 20 studies that were used to inform the question that we addressed. I'll turn it over to Sumita to add further.

Dr Khatri: Sure. It was quite a herculean task. I think you and I felt like we were sitting pretty for a while, while the methodologists were working away. We knew when they came back to us, our work would begin. They really put so much work into this. It was amazing.

They have programs, but they had to do a lot by hand too. Then what we found as a result drum‑roll is that these studies showed that with a moderate certainty of evidence, two things, that asthma exacerbations were lower and favored the intervention of measuring FeNO, and that oral steroid use was lower and favored the intervention of measuring FeNO for that.

More specifically for the asthma exacerbation outcome, that there were 10 trials with moderate certainty and that showed that the risk ratio was .72 with the absolute effect with FeNO having 111 fewer exacerbations per thousand people.

Meanwhile, the oral steroid use study was lower and showed that in six trials with moderate certainty that the risk ratio was .79 with the absolute effect of 69 fewer per thousand. The panel concluded that the balance of effect probably favors this intervention due to the moderate costs and probable favorite cost effectiveness.

Although this is a conditional recommendation, that we felt that the risk versus benefit was reasonable for these kind of outcomes, where we know that there's so much morbidity, not only for kids in particular where the kids' studies, the children studies showed this more of a stronger link.

For kids and adults the oral corticosteroid usage causes so much morbidity. Of course, exacerbations result in so much symptomatology and healthcare utilization, which we couldn't quite measure specifically.

We could extrapolate that these were two very important outcomes that would be meaningful for clinicians and meaningful for patients. We were trying to keep the patient at the center of our analysis.

Dr Hallstrand: One thing I might just comment and add to that is that we provided a conditional recommendation, which maybe makes it sound like we're uncertain about the recommendation, but that conditional recommendation is based on the strength of the evidence.

The fact that we only had 20 trials that very specifically address in a rigorous manner that the question is the reason for a conditional recommendation.

Had there been more studies, we would have been able to be more certain about the outcome, but as Dr Khatri was saying, the difference is the reduction in exacerbation frequency and oral corticosteroid use are very large effects.

We're only saying that we're not as certain as we might like to be about these effects that the effects of using exhaled nitric oxide to guide asthma treatment really is associated with very large effects as far as reducing the things that we thought as clinicians were the most important, which are exacerbation frequency for all corticosteroid use and similar outcomes.

Jessica: What gaps exist in this research?

Dr Hallstrand: Our aspirational goal in addressing the one question about the use of exhaled nitric oxide in making decisions in the clinic is in part the absence of specific cut points.

Since the initial guideline, where there are these broad categories, a lot of the research has used more narrowly defined cut points. However, the studies were not conducted in a manner in which we could combine that data to give a specific cut point with an action, which is why clinical judgment is an essential component.

We can't say that if your exhaled nitric oxide is 40, you have a specific action. Part of that is because there are some individuals with asthma.

As we have learned over the last 20 years about subgroups of patients with asthma. Some groups of patients with asthma have elevated exhaled nitric oxide that tracks very well with this severity of their disease and the activity of their disease.

There's other groups of patients, especially obesity‑associated asthma and people that smoke as part of their disease, and those people tend to have lower exhaled nitric oxide. It makes it less clear about exhaled nitric oxide and inflammation.

We were unable to identify specific cut points, so that's a gap that could potentially be addressed if there are more studies that look at gap, that look at cut points and specific subgroups.

As is right now, clinical judgment is needed identifying who that patient is that you're seeing and what their exhaled nitric oxide and integrating that together. I think that's a big gap.

I'll let Dr Khatri talk about that and then I'll talk about addressing the other questions as well.

Dr Khatri: As you were mentioning all of this, I was also thinking that a gap is the pragmatic trials that you were talking about initially that how is somebody who's nitric oxide measurement naive and establishing a diagnosis of asthma, and over time as you treat them how does it change.

Also, when we look at all of the other measures like asthma control and oral cortico steroid use, better logging of that information would be helpful during these clinical trials.

You know that the Asthma Control Questionnaire as well as the ACT, Asthma Control Test, we were not able to pull those numbers, because perhaps we might have seen something for asthma control.

I would recommend for any future investigators use both of those metrics, and then perhaps we can use them and qualitatively and quantitatively study them in the future. That as well as biomarker, profiling, and phenotyping as we go along and looking at nitric oxide that way. Those were my other thoughts as far as how I would do it a little bit differently.

Dr Hallstrand: Exactly. As we both know when we're in the clinic, sometimes exhaled nitric oxide is extremely helpful. Oftentimes, you know that when you first measure it in someone, and their history, which allows us to use that clinical judgment.

There aren't studies that specifically excluded people that we expect to have a low exhaled nitric oxide such as obesity‑associated asthma, which is actually a fairly large fraction of the patients with asthma.

I think one gap in the knowledge that we didn't address very clearly in this guideline is that if you have a subgroup in which you expect there to be elevated exhaled nitric oxide, how effective is it in that subgroup. It's likely extremely effective in that group.

Another thing that we did in addressing the guidelines is how effective this is for using the newer biologic agents.

In some cases, we would anticipate that it'll be quite effective at guiding therapy for type 2 asthma, but the other big gap or the two other big questions, which is how effective is it to monitor asthma.

Once you measure it in the clinic, then subsequently measuring it again, how effective is it in that instance. We didn't address that systematically in this guideline, and maybe a future guideline would be on that topic.

The other topic which is making a diagnosis of asthma, which is really a key under-recognized area that many people, especially with mild‑to‑moderate asthma who are diagnosed or diagnosed based largely on their symptoms and in some cases based on their lung function.

Tetra nitric oxide is one initial diagnostic test in addition to other tests such as bronchoprovocation tests, and how well it works versus using other tests is a key gap in the knowledge as well.

Jessica: What would you all say are the overall take home messages from our conversation today?

Dr Khatri: I'll take a stab at the take-home message I'd like clinicians to have. If they weren't going to use their clinical judgements, similar to how we've outlined in figure two, that the methodologist helped put this into statistical words.

I like pictures. I need to imagine something as I'm seeing a patient so that's why I was hell‑bent on [laughs] having a figure like this. What the methodologist said is unique.

What you actually mean is that the decision of an individual clinician to use a lower phenyl value to identify persistent inflammation means that the sensitivity to detect inflammation is being prioritized over the specificity that change and treatment will make a difference.

Similarly, a decision to use a higher phenyl value assigns greater priority to the specificity of the finding, at the cost of reducing sensitivity. It's just a beautiful way of wrapping it together.

You may have a risk-benefit slide‑rule that you're using. What is the benefit versus the risk? What is the outcome I want versus the avoidance of a poor outcome?

I'm hoping that this is helpful. I've really appreciated the opportunity to work with Teal on this. I think we brought very different skill sets that were also complimentary to hopefully contribute to the literature. I couldn't be more proud of what we've done together.

Dr Hallstrand: I would agree that this process that we went through together was extremely effective at combining statistical know‑how, and clinical judgment, and clinical background to come up with a useful and clear recommendation.

It's been a great process, and it's been wonderful working with you, Sumita, as well as all the wonderful team.

Dr Khatri: International team, yes.

Dr Hallstrand: [laughs]

Jessica: Thank you both for joining us. We appreciate you on the podcast today, and for all of your hard work on this.

Dr Khatri: Thank you. It was a pleasure to join you today.

Dr Hallstrand: Yes, it was a pleasure to be on with you today. Thank you.