Measuring airway inflammation when diagnosing and treating asthma patients

insights from industryCarol StonhamHeadLocality Based FeNO Referral Service

In this interview, Carol Stonham, the head of a Locality Based FeNO referral service, talks to NewsMed about measuring airway inflammation when diagnosing and treating asthma patients.

Could you start by giving our readers an overview of asthma and its typical treatments?

I'm sure the majority of your readers are familiar with the main symptoms of asthma. Still, it is important to clearly define what asthma is and what features it has, particularly when we are thinking about where fractional exhaled nitric oxide (FeNO) fits into this definition.

When diagnosing asthma in patients, we must be sure of the presence of more than one of its features: breathlessness, wheezing, chest tightness, or cough.

Variable airflow obstruction is the classic symptom, but more recent definitions from the British Thoracic Society (BTS) highlight that both adults and children will have features of airway hyper-responsiveness and airway inflammation.

Eosinophilic airway inflammation is what we are most interested in when looking at FeNO. Eosinophilic airway inflammation is key because we know that it is very sensitive to the effects of inhaled steroids.

Patients with asthma have a genetic predisposition that reacts to something in the environment, resulting in inflammation that causes airway hyper-responsiveness and reversible airway obstruction. This reversible airway obstruction is responsible for the clinical symptoms just mentioned - the cough, wheeze, and shortness of breath.

We know that inflammation in asthma patients affects the lining of the airways, causing these to become inflamed and narrowing the lumen, making breathing more difficult. Patients also exhibit bronchospasm when the airways are inflamed.

Patients do not always understand that the underlying mechanism is inflammation, and many connect their asthma symptoms to the bronchospasm. Often this is because patients have not had this explained to them.

We find a lot of patients tend to be over-reliant on using their salbutamol inhaler and tend to be less compliant when using their inhaled steroids, which are designed to address the inflammation.

Where does FeNO fit into the diagnosis and treatment of asthma?

The role of FeNO can be understood by looking at a typical process. If an allergen hits the dendritic cell, this causes a release of B&T and T-cell mediators, triggering eosinophils, which, in turn, causes inflammation.

Image Credit: Bedfont Scientific

As this inflammatory cascade is happening underneath the surface of the airway lining, increased nitric oxide is being produced at the mucus membrane.

We know if there is eosinophilic airway inflammation, there is also a release of nitric oxide. We also know that the more eosinophilic airway inflammation there is, the more nitric oxide is released via the exhaled breath.

There are other factors that can influence the amount of NO that a patient breathes out; for example, the amount of available lung surface area, other illnesses like rhinitis, the patient's diet, or whether they smoke.

How does this awareness of FeNO's connection with inflammation link into the BTS guidelines on asthma diagnosis?

The BTS guidelines tell us that the diagnosis of asthma is a clinical one. The absence of consistent gold standard diagnostic criteria means it is not possible to make equivocal evidence-based recommendations on how to make a diagnosis of asthma.

BTS has approached diagnosis in a pragmatic way by establishing diagnosis based on current evidence and the collective experience of the guideline development group.

This has led BTS to a different conclusion from that of The National Institute for Health and Care Excellence (NICE), which does not take into account collective experience. Rather, NICE considers the evidence base and cost-effective modeling.

BTS tells us to look at the history and previous records of the patient in order to evaluate recurrent episodes of symptoms, key variability, and the absence of anything else that could account for the diagnosis.

BTS guidelines also recommend that to ensure consistency, a diagnosis should be based on records provided by a healthcare professional as opposed to the patient, for example, records of atopy, historic evidence of peak flow, or FEV1.

Once this is done, the probability of a patient having asthma is assessed, and a trial of treatment is conducted if there is a high probability. This typically involves the provision of an appropriate steroid inhaler and a review six to eight weeks later to see how the patient has responded to the treatment.

FeNO should be evaluated initially as part of standard testing, and this can be followed by a spirometry or peak flow test. It is important to note that performing spirometry first can artificially skew FeNO results – the order of these tests is an important consideration.

A symptom score is recorded to measure against later. When reviewing the patient after a trial of treatment, if the symptoms have improved in keeping with a diagnosis of asthma, we can titrate the patient's dose, check their inhaler technique, start a supported asthma self-management plan and monitor this.

After this process, it may become clear that the patient has something other than asthma that requires further investigation. FeNo is also an excellent choice where a diagnosis is unclear, and medical professionals are faced with a dilemma where the patient could have asthma, but more objective evidence is required for it to be confirmed. In these instances, FeNo can also be used to provide further insight into the patient’s condition.

This is the stage of the diagnosis where FeNO excels. FeNO has been recommended in both the BTS and NICE guidelines for some time.

FeNO can be used to look for specific eosinophilic airway inflammation. It is possible to look at blood eosinophils for more generalized eosinophilia, or skin prick testing and blood IgEs are an option to look for more generalized atopy.

Blood eosinophils are a generalized marker for localized disease; however, a number of factors can influence these results, including medication, specific illnesses, and parasitic infection.

NICE provides an algorithm that can be used to interpret FeNO results. This states that a FeNO score of more than 40ppb (parts per billion) supports a diagnosis of asthma, though additional investigation may be required to confirm this.

Adults and children's scores will differ because adults have bigger lungs. An adult presenting without a diagnosis, and a FeNO of less than 25ppb does not support a diagnosis of allergic (eosphillic) asthma. It can be safely assumed that giving them an inhaled steroid is unlikely to help their symptoms.

If their FeNO is more than 50ppb and the patient is symptomatic, they are likely to benefit from the introduction of inhaled steroids, which supports a diagnosis of asthma.

A FeNO score of more than 50ppb with no other context does not automatically mean a patient has asthma – this score is still a part of the diagnostic jigsaw and should be evaluated along with history and results of other lung function tests such as spirometry.

FeNO remains the preferred option because it is a localized marker for localized disease, and the results are almost instantaneous. Once FeNO results are assessed, the patient's history can be re-evaluated alongside any other investigations (such as spirometry, etc.) before making a more informed diagnosis of suspected asthma.

What role does FeNO play in asthma management beyond diagnosis, and can you provide a typical example scenario?

FeNO can be applied to support patients to better manage eosinophilic asthma when they present with worsening symptoms. The use of an Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ) is also useful in this situation, and these tools should always be used as they provide good insight into the patient's condition and asthma control.

As an example, an adult male comes into surgery. He is 47 and has had asthma since he was 27. The patient is a non-smoker. He uses inhaled Beclomethasone pMDI - two puffs twice a day, as well as an AeroChamber.

He has been increasingly symptomatic over the last six weeks and is occasionally waking up at night because of his asthma. He also needs to use his rescue inhaler most days, but today he has come for a routine appointment - not an emergency situation.

BTS tells us to add in a long-acting beta2-agonist, review this and continue this treatment if effective. If it is ineffective, the guidance advises stopping this treatment and increasing inhaled steroid; or if it is partially effective, to continue the beta2-agonist  and increase inhaled steroid then review again.

If the asthma is still not controlled, medical professionals will generally consider other therapies like montelukast or theophylline.

Unfortunately, there is a lot of trial and error in this process, and it is highly reliant on the patients' capacity to report their symptoms accurately and whether or not treatments are effective. A more objective means of evaluating the treatment decision is necessary for these circumstances – this is where FeNo can be extremely useful.

Patients with asthma are often experts in their disease because they live with it. Medical professionals are only receiving a very small snapshot into this.

Even when using the appropriate tools and tests, it is important to ask the patient questions. For example, asking them if their current symptoms are different, if they have presented before, what triggered them, etc. Tests can be used to investigate this further where appropriate, for example, spirometry or FeNO tests.

How important is it to measure airway inflammation when diagnosing and treating asthma patients?

It is possible to measure airway obstruction via spirometry, and we can measure clinical symptoms via questionnaires, consultations, or doing an ACT.

Airway hyper-responsiveness can be measured via challenge testing, though this is rarely done in primary care. We do not typically measure airway inflammation, but that is the key to understanding a patient's asthma symptoms. This is the piece of the jigsaw that we have been missing.

As I previously mentioned, airway inflammation occurring underneath the surface hits the mucus membrane and causes the release of nitric oxide, which the patient blows out every time they breathe.

Capturing this information in a very simple way can tell us whether the airways are inflamed or whether it is bronchospasm causing the problem. This information can then guide our treatment decisions.

Continuing with the patient example from earlier on, spirometry performed on this patient came back as normal. His FEV1 was 90%, as predicted, and his ratio was 78%.

Often the patient presents when they are feeling well, and the patient in this example has a good inhaler technique. There are also no new triggers, but there is a history of recurrent episodes of a prolonged cough with sputum. The patient reports that this mostly happens after he gets an upper respiratory tract infection.

We know that environmental factors cause airway inflammation, which in turn causes airway hyper-responsiveness and airway obstruction, which in turn causes clinical symptoms.

On this occasion, however, it was not an upper respiratory tract infection that triggered the patient's symptoms - it was something that just developed over a period of time. The patient's FeNO was found to be 72ppb.

Following the BTS guidelines in this instance would see the patient being given a long-acting beta-agonist (LABA) in addition to the inhaled steroid, but this does not consider that his airways are very inflamed. Knowing this would prompt a change in approach, focusing on addressing the airway inflammation.

How does the use of FeNO testing align with the concept of personalized care?

FeNO testing is a key component of delivering personalized care for asthma patients. Personalized care is about getting it right for the person in front of you, rather than strictly following the guidelines.

This can be illustrated by looking at a small study of 50 patients in America. The study involved an allergy clinic specializing in nothing but allergy treatment — all 50 patients presented with asthma.

The clinic saw the patients and took their histories. All the patients with asthma were increasingly symptomatic, and the clinic made the treatment decisions without FeNO. They then measured FeNO, and it was only in 50% of the cases that the clinic followed their original treatment decision.

Another study by Liam Heeney saw a research fellow visiting patients at home to watch them use their inhaled steroids and measure their FeNO. The patients were then left with the machine to track this over time. It was clear which patients had stopped using their inhaled steroids because their FeNO immediately started to climb.

Used in this way, FeNO is a useful tool for ensuring adherence to treatment and can demonstrate the impact of non-adherence in a measurable way, allowing medical professionals to work in partnership with a patient and open up a dialog about the importance of using their inhalers.

Can FeNO be used with patients looking to step down their inhaled steroid use?

Stepping down patients can be challenging, but patients on high-dose steroids must be reviewed regularly to look at options for stepping them down where possible. The goal is to maintain patients on the lowest possible dose of inhaled steroids that still effectively controls the disease.

Image Credit: Bedfont Scientific

We know that reductions in inhaled steroids should be done slowly and with care. The BTS guidelines only quote one paper on this, so there is little evidence to convince patients to reduce their steroid dose when their asthma is well controlled.

Stepping down involves a degree of planning in advance, factoring in any seasonal or environmental triggers or significant life events which may impact their symptoms.  Patients must also be asymptomatic for at least three months before considering reducing steroid doses.

FeNO can be used as a tool throughout this process to evaluate patients' progress. The NICE guidelines are also helpful here. For example, if a patient's FeNO is less than 25ppb, they have been well for three months, and are not going into a difficult season or challenging time, then steroid reduction may be an option.

FeNO testing is important because there may be a discrepancy between how a patient reports feeling and the measured inflammation of their airways.

For example, a study was conducted of 40 children who were stepped down using FeNO as a guide to look for a predictor for risk of relapse.

The children were found to have good baselines, which were rechecked at two and four weeks. Where the children were set to relapse, the FeNO measurements went back up again, while those not set to relapse stayed around the same level.

This study showed that FeNO could provide valuable insight into the stepping down process, allowing it to be managed more safely.

What impact does regularly using FeNO measurements have on your clinic in practice, and has this been impacted by COVID-19?

The clinic I have been running over the last few years has operated on different funding models, but over the past year, it has operated on an invest-to-save business case based on the figures from the previous year. I see patients from 19 practices – a practice population base of 93,000 patients.

I have been able to show that savings were made in the prescribing budget. Reducing inappropriate prescribing, step down, and more accurate asthma diagnosis has been enough to fund the business case for a year.

It has not saved money, but it has not cost anything – it has been cost-neutral. The clinic works by primary care referral so that any primary care clinician can refer to me.

My clinic provides diagnosis using intermediate probability of asthma adhering to BTS guidelines, step up advice, step down advice, and patient education. Patients with adherence issues and patients with difficult but not severe asthma require different approaches and are seen in the clinic.

My clinic was suspended at the start of the COVID-19 pandemic, and was restarted back in September 2021. COVID has highlighted one of the longstanding challenges around asthma diagnosis regarding whether FeNO was considered an aerosol generating procedure (AGP).

Thankfully, FeNO is not considered aerosol generating because it is a low-effort procedure that does not induce cough. The filters in use are also able to trap the virus. So long as a COVID check has been done with the patient and they are not showing any symptoms, then FeNO should be considered very low risk.

The machines require cleaning between patients, and single-use consumables should not be reused, but this should be standard practice regardless.

Bedfont are currently working with a research group in Brazil to explore the relationship between FeNO and COVID-19. That research is still recruiting and gathering data, so there are no results at the moment, but this is currently being investigated and looked into.

I think the most crucial thing to consider is how important it is to not lose the patient's perspective and voice.

We know that asthma still has a huge symptom burden and that patients still die from asthma, so any tools that we can leverage to manage this condition better, and support these patients are vital.

About Carol Stonham


Following 26 years working in general practice Carol now works at Gloucestershire CCG on the

Respiratory Clinical Programme Group and runs a locality-based asthma FeNO service.

Carol is current Executive Chair of PCRS – the first non-doctor and first female to take the chair. She is also a director of the UK Lung Cancer Coalition, and primary care nurse representative for the UK Inhaler Group and National Asthma and COPD Audit and is chairing NHSE LTP Early and Accurate Diagnosis work stream. She also co-chairs the Lung Health Taskforce early and accurate diagnosis group.

Carol received Queen’s Nurse award in 2007. In 2016 was awarded an MBE in the Queen’s New Year Honours list for Services to Nursing and Healthcare.

About Bedfont® Scientific

Bedfont® Scientific has specialized in the design and manufacture of exhaled breath and gas monitoring instruments since 1976.

For medical gas monitoring, their Medi-Gas Check medical pipeline testing range verifies not only the quantity but also the quality of gas administered to patients.

Bedfont's breath analyzers include carbon monoxide (CO) monitors such as the Smokerlyzer®, used for smoking cessation, and the ToxCO®, used by emergency services, to diagnose CO poisoning.

The NObreath® FeNO monitor provides accurate analysis of airway inflammation for the control of asthma, and the Gastrolyzer® range aids in the detection of gastrointestinal disorders and food intolerances. Quick and non-invasive breath analysis is the new blood test.



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The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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