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Primarily, Professor Price said, testing FeNO levels in patients with respiratory disease symptoms has shown real value in decision-making when it comes to determining a patient’s suitability for inhaled corticosteroids (ICS).
There is also evidence that FeNO is a significant help with adherence. Professor Price explained that many physicians will have found themselves in consultation with someone whose asthma seems to be poorly controlled but who says they are taking their medication. FeNO values are a clear indicator of this and can be measured at the point-of-care, giving actionable results at the patient’s appointment. Professor Price said: “Patients said they were adhering and yet their FeNO was sky-high – doctors would say “you can’t really be taking your inhaled steroids” and they showed an increase in adherence after that.” Knowing their FeNO number and watching how it can increase or decrease through follow-up visits helps with patient education, which in turn, often leads to greater compliance.
Professor Price mentioned a retrospective study that was carried out looking at patients’ current asthma control and prior exacerbations versus their FeNO and blood eosinophil count.1 Both FeNO and blood eosinophils are predictors of asthma and are clearly very helpful in determining exacerbation risk, Professor Price pointed out.
“Most interesting for me was where we randomised patients to ICS or placebo with non-specific respiratory symptoms, such as cough, wheeze and shortness of breath, but without objective reversibility supporting a diagnosis of asthma. These are patients whose doctors are undecided about a trial of ICS. What we saw were two independent predictors of response – FeNO, the strongest predictor, and blood eosinophil count – both predicting a symptomatic response to ICS over placebo at one month. That was very powerful for me – if you have a patient and you don’t know what’s going on with them, this is a great way to work out whether you need to give them ICS.”
Another important piece of evidence came from the International Severe Asthma Registry2 where, Professor Price explained, there is an algorithm looking at eosinophilic asthma. “We use eosinophil counts and FeNO, and the big message is that only about 5% of people with severe asthma were non-eosinophilic if you include FeNO in that definition. The vast majority have T2 disease and will respond to T2 therapies – ICS and biologic therapies. Those are some of the key real-life studies.”
Clearly there is a population within COPD who have T2 disease, Professor Price said. Even on average, the blood eosinophil count is higher in patients with COPD than in a non-COPD population, so they have inflammatory disease. “My hunch is that FeNO would predict response to ICS in COPD and may also predict the response to some of the biologics. There are emerging studies coming that will look at that.”
Cystic fibrosis is a harder one, Professor Price noted. “Some of those cases will have an asthma element. What we are looking for is treatable traits. One of the pivotal things that has been happening over the last 10 years – in asthma originally but certainly in COPD as well – is “what can we treat in this patient?” You can give bronchodilators to those with broncho-constriction but what about knowing who will benefit from the T2 therapies – ICS and biologics? I think [FeNO] will potentially be very useful there.”
Real-world data is always interesting, Professor Price pointed out. “Our institute is called the Observational and Pragmatic Research Institute and we’ve put those two words in very deliberately. There are the observational data sets and then there are the pragmatic trials, which are more like real-life clinical trials.” Observational data is really useful for predictive work and Professor Price said researchers had been able to look at FeNO and eosinophil counts to show that they are independent predictors of exacerbations. “Where it gets a little bit harder is with taking a measurement because doctors’ behaviour changes. There is a series of studies looking at the use of FeNO and eosinophil counts in real-life settings where doctors and patients are made aware of the findings. As soon as you tell people they’ve got a high FeNO count and that it could be related to them not taking their medicine, suddenly you’ve changed the whole game!”
It can be difficult to look for predictive results. “You have to try to generate real-life data with clinical equipoise because otherwise it’s very difficult. Particularly when you start to look at drug studies in real-life datasets because you need the data,” said Professor Price. He noted that different doctors obtain the same data, they see the same type of patients, but they do different things. “Effectively, you’ve got a randomised trial in real life. If that doesn’t exist and, for instance, you only do a test at a certain point in the pathway, it’s not very helpful.”
“For me, one of the big challenges is that, to date, our international guidelines or strategies have left the biomarker assessment at the severe or difficult-to-treat asthma end, when it’s all about helping to select the right treatment,” said Professor Price, stating that one of the most important aspects is to understand the beginning of the asthma journey. The goal is to establish who is a high-risk patient, who would benefit from better intervention and identifying patients who do not exhibit much evidence of T2 disease. “Are we really sure they’ve got asthma? The body of evidence we have on FeNO is pretty restricted in observational studies, in real life, in milder asthma, whereas we’re starting to build the evidence in severe asthma.”
Professor Price said the challenge lies in finding enough patients to really assess the value of the biomarkers. “You do need big numbers. Patients have to be well characterised and you have to follow them up for long enough. There is always the challenge of getting enough big data in those real-life studies that enables you to do those additional analyses.
“That’s where more real-life observational data comes in. I got quite excited last year when quite a big group in the UK encouraged the use of FeNO in primary care but COVID messed that up. I was hoping that with data coded in electronic medical records, we would be able to build up very big data sets. We are starting to see that data but we do need that type of big data to answer the bigger questions.”
Electronic medical records are increasingly valuable in the UK and to some extent in the US, Professor Price noted. “We have 17 million patients in the Optimum Patient Care Research Database and a median follow-up of 27 years of data so we know about people over a very long period. The more information you can get in there, the better. Doctors in the UK have been encouraged to record more standardised data in asthma. If FeNO had been part of that, it would be absolutely phenomenal. We need more information in those settings.”
“Doctors who use FeNO can never do without it!”
“Doctors who use FeNO can never do without it!” said Professor Price. “It’s quite hard to quantify why that is and that’s what we tried to do among primary care physicians with a respiratory interest. What came through was that they worked out where FeNO was really useful. “Should we be treating this with ICS or shouldn’t we?” “Maybe we should be increasing the dose – or is it just poor adherence?” FeNO is very, very useful in those places.
“From a research perspective, it would be incredibly valuable to understand [more about FeNO]. We know that eosinophils are incredibly helpful in predicting the beneficial response to ICS in COPD and I am sure FeNO would be similarly useful.”
Professor Price highlighted further research that is helping. “We have seen from the NOVELTY study of around 13,000 patients with asthma, COPD or unsure diagnosis, that reversibility was not predictive of who would have an asthma or COPD label,” he said.3 “We spend a lot of time doing tests that don’t really make the diagnosis. FeNO is incredibly valuable in getting into that treatable trait, as is a blood eosinophil count. I can’t do without them for research and I don’t think you can do without them in clinical practice once you’ve used them.”
“Patients love it, I have to say. People like to have a number – it’s very nice to be able to look at that and to look at how it changes in response to therapy. It’s very nice to be able to show patients that “your FeNO was 50, we started you on inhalers and look, it’s down to 20. Your symptoms are better too”. This shows the value. “You’ve calmed down the inflammation in your lungs and we’ve got to carry on with this type of treatment”. That’s a really cool way to start.”
FeNO is very useful in new patients when titrating dosage up or down, said Professor Price. It's also beneficial in primary care when physicians are considering referral. If either FeNO or blood eosinophil count is up, he said, a patient whose asthma is uncontrolled with their therapy might do very well with a biologic.
Professor price added: “From a specialist perspective, I don’t know how anyone can manage without FeNO in severe asthma today. It’s increasingly becoming a very normal test, at least as part of the first assessment for patients with severe asthma. Ideally, we would have the longitudinal data because again, it’s very nice if you start people on drugs that may lower [their FeNO] and we do see it drop. Interestingly, not just with the cases where you would expect it, such as with an anti-IL-4 or 13, but we see it dropping with anti-IL 5s too.”
The views and opinions expressed in this interview are those of Professor Price.
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1.Looijmang-van den Akker I et al. Overdiagnosis of asthma in children in primary care: a retrospective analysis. Br J Gen Pract. 2016 66 (644): e152-e157
2.Aaron SD et al. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017 317(3): 269-279
3.Smith AD et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med. 2004 169: 473-478.
4.Wagener AH et al. External validation of blood eosinophils, FeNO and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015 70: 115-120.
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6.GINA. Diagnosis and Management of Difficult-to-treat and Severe Asthma in adolescent and adult patients, a pocket guide. 2020.
7. Corren J et al. Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma. J Allergy Clin Immunol Pract. 2020 8(2): 516-526.