NIHR Signal The nitric oxide breath test offers little benefit when monitoring asthma

Published on 10 January 2017

Using exhaled nitric oxide levels to guide the dose of asthma medication at regular clinic visits may reduce flare-ups but does not improve overall symptoms or quality of life. In this review hospitalisations and the total inhaled steroid doses were unaffected by the intervention.

Measuring the amount of fractional exhaled nitric oxide (FeNO) in the breath of people with asthma detects lung inflammation. If inflammation increases, this may indicate that a flare-up is likely and preventative action can be taken. The aim is to ensure medication corresponds to symptom severity, the ideal being the minimum dose needed to control symptoms.

The usual monitoring strategy consists of subjective (such as self-reporting) and objective (such as how quickly air can be expelled from the lungs) measures. Guidelines emphasise the use of self-management treatment plans based on symptoms and possibly monitoring airway peak flow at home. FeNO measurement in the clinic is a more recent alternative.

Whilst it may offer a warning of flare-ups, its greater cost and lack of impact upon other outcomes mean it is unlikely to be worth using in the majority of cases.

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Why was this study needed?

Asthma costs the NHS around one billion pounds a year and one in 12 adults live with the condition. Whist there is no cure; it can usually be well managed with the right treatment strategy. Medication needs to be reviewed regularly and increased (stepped up) or decreased (stepped down) according to symptom severity. This strategy aims to minimise exposure to medications such as steroids.

Even when the condition is monitored, people can have flare-ups (exacerbations). The worsening of symptoms and asthma attacks can have a major impact upon quality of life. As a result, exploring ways to more accurately predict and thus prevent flare-ups is important in terms of patient, as well as cost, related outcomes.

Although FeNO is a newer and potentially more sensitive way to track lung inflammation than existing techniques, it is more expensive. This systematic review sought to ascertain whether the additional cost is justified.

What did this study do?

This systematic review included seven randomised controlled trials of 1,700 adults with asthma aged 28 to 54. It compared adjustment of asthma medications using FeNO compared to standard measures based on clinical symptoms and signs according to asthma guidelines. Study duration ranged from four to 12 months. One study was conducted in the UK. The patients had to attend a clinic about every one to two months, which may not represent usual UK practice and it is unclear how well people were managed in the control group.

The quality of evidence was graded moderate for the exacerbation outcome. Some intervention studies included FeNO as part of their management algorithm rather than as the sole strategy. The differences between medication used and asthma severity varied between trials and limited the pooling of results in the meta-analysis. These factors mean some caution should be applied to the findings though they can still be seen as reliable.

What did it find?

  • People in the FeNO group were less likely to have an exacerbation over a year. They occurred in 17 out of 100 people in the FeNO group compared to 25 out of 100 in the control group (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.43 to 0.84). 5 trials. The FeNO group had 41% fewer exacerbations than the control group, who had on average 0.23 to 0.9 exacerbations over the year (rate ratio [RR] 0.59, 95% CI 0.45 to 0.77). Twelve people would need to be treated over 52 weeks for one person to benefit (number needed to treat to benefit 12, 95% CI 8 to 32).
  • No difference was found for more severe exacerbations, requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48).
  • No difference was found between groups for Asthma Symptom Score, range 5 to 25 with lower scores denoting worse symptoms (mean difference ‑0.08, 95% CI c‑0.18 to 0.01).
  • There was no difference in Asthma Quality of Life Questionnaire score (mean difference 0.00, 95% CI ‑0.10 to 0.10).

What does current guidance say on this issue?

The 2016 British Thoracic Society and Scottish Intercollegiate Guidelines Network guideline for the management of asthma states that diagnosis of asthma relies on a combination of symptoms, signs and tests as there is no gold standard measurement. They report that the FeNO test is not particularly accurate; one in five adults with a positive test will not have asthma and one in five with a negative test will have asthma. It is recommended as an optional investigation if the diagnosis is in doubt. This is to look for inflammation of the airways by eosinophils, white blood cells that are involved in allergic reactions.

The guideline notes the potential for tests such as FeNO that measure airway inflammation to improve management strategies, especially for people with more severe asthma. However, they do not yet recommend one test over another.

What are the implications?

On the basis of this review it does not appear that current practice should change. FeNO may help reduce flare-ups, but this benefit does not seem to extend to other important outcomes. It also requires frequent clinic attendance and the benefit could be due to poor use of existing strategies. This means in most instances the increased cost may not be warranted, but that it could remain a specialist test. For example, for those patients that suffer the distress of repeated flare-ups, FeNO may be an option.

A NICE asthma management guideline, currently in development, is looking into the impact and feasibility of implementing objective tests such as FeNO in primary care. It will be interesting to see what the conclusions of this will be in light of the limitations of the evidence base included in this review.

Citation and Funding

Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev. 2016;9:CD011440. [Epub ahead of print].

Cochrane UK and the Airways Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

Asthma UK. How is asthma treated. London: Asthma UK; 2016.

BTS/SIGN. Guideline for the management of asthma. London: British Thoracic Society/Edinburgh: Scottish Intercollegiate Guidelines Network; 2016.

Why was this study needed?

Asthma costs the NHS around one billion pounds a year and one in 12 adults live with the condition. Whist there is no cure; it can usually be well managed with the right treatment strategy. Medication needs to be reviewed regularly and increased (stepped up) or decreased (stepped down) according to symptom severity. This strategy aims to minimise exposure to medications such as steroids.

Even when the condition is monitored, people can have flare-ups (exacerbations). The worsening of symptoms and asthma attacks can have a major impact upon quality of life. As a result, exploring ways to more accurately predict and thus prevent flare-ups is important in terms of patient, as well as cost, related outcomes.

Although FeNO is a newer and potentially more sensitive way to track lung inflammation than existing techniques, it is more expensive. This systematic review sought to ascertain whether the additional cost is justified.

What did this study do?

This systematic review included seven randomised controlled trials of 1,700 adults with asthma aged 28 to 54. It compared adjustment of asthma medications using FeNO compared to standard measures based on clinical symptoms and signs according to asthma guidelines. Study duration ranged from four to 12 months. One study was conducted in the UK. The patients had to attend a clinic about every one to two months, which may not represent usual UK practice and it is unclear how well people were managed in the control group.

The quality of evidence was graded moderate for the exacerbation outcome. Some intervention studies included FeNO as part of their management algorithm rather than as the sole strategy. The differences between medication used and asthma severity varied between trials and limited the pooling of results in the meta-analysis. These factors mean some caution should be applied to the findings though they can still be seen as reliable.

What did it find?

  • People in the FeNO group were less likely to have an exacerbation over a year. They occurred in 17 out of 100 people in the FeNO group compared to 25 out of 100 in the control group (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.43 to 0.84). 5 trials. The FeNO group had 41% fewer exacerbations than the control group, who had on average 0.23 to 0.9 exacerbations over the year (rate ratio [RR] 0.59, 95% CI 0.45 to 0.77). Twelve people would need to be treated over 52 weeks for one person to benefit (number needed to treat to benefit 12, 95% CI 8 to 32).
  • No difference was found for more severe exacerbations, requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48).
  • No difference was found between groups for Asthma Symptom Score, range 5 to 25 with lower scores denoting worse symptoms (mean difference ‑0.08, 95% CI c‑0.18 to 0.01).
  • There was no difference in Asthma Quality of Life Questionnaire score (mean difference 0.00, 95% CI ‑0.10 to 0.10).

What does current guidance say on this issue?

The 2016 British Thoracic Society and Scottish Intercollegiate Guidelines Network guideline for the management of asthma states that diagnosis of asthma relies on a combination of symptoms, signs and tests as there is no gold standard measurement. They report that the FeNO test is not particularly accurate; one in five adults with a positive test will not have asthma and one in five with a negative test will have asthma. It is recommended as an optional investigation if the diagnosis is in doubt. This is to look for inflammation of the airways by eosinophils, white blood cells that are involved in allergic reactions.

The guideline notes the potential for tests such as FeNO that measure airway inflammation to improve management strategies, especially for people with more severe asthma. However, they do not yet recommend one test over another.

What are the implications?

On the basis of this review it does not appear that current practice should change. FeNO may help reduce flare-ups, but this benefit does not seem to extend to other important outcomes. It also requires frequent clinic attendance and the benefit could be due to poor use of existing strategies. This means in most instances the increased cost may not be warranted, but that it could remain a specialist test. For example, for those patients that suffer the distress of repeated flare-ups, FeNO may be an option.

A NICE asthma management guideline, currently in development, is looking into the impact and feasibility of implementing objective tests such as FeNO in primary care. It will be interesting to see what the conclusions of this will be in light of the limitations of the evidence base included in this review.

Citation and Funding

Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev. 2016;9:CD011440. [Epub ahead of print].

Cochrane UK and the Airways Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

Asthma UK. How is asthma treated. London: Asthma UK; 2016.

BTS/SIGN. Guideline for the management of asthma. London: British Thoracic Society/Edinburgh: Scottish Intercollegiate Guidelines Network; 2016.

Exhaled nitric oxide levels to guide treatment for adults with asthma

Published on 2 September 2016

Petsky, H. L.,Kew, K. M.,Turner, C.,Chang, A. B.

Cochrane Database Syst Rev Volume 9 , 2016

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic inflammation (for example sputum eosinophils). OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related outcomes in adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. We independently selected relevant studies in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving responses from four. MAIN RESULTS: We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit).We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. AUTHORS' CONCLUSIONS: With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

Expert commentary

Airways inflammation in asthma increases nitric oxide synthase and thereby FeNO. FeNO has been advocated as an objective marker of disease severity and compliance with therapy (which reduces it).

These studies of variable quality and duration in adult asthmatic patients suggest that additional FeNO monitoring may reduce episodes of aberrant lung function, but not unplanned care, oral corticosteroid usage or day to day symptoms.

Although FeNO is now relatively cheap and convenient to measure, its precise benefits in asthma management remain to be defined in more clearly focussed studies.

Christopher Corrigan, Professor of Asthma, Allergy and Immunology, King’s College London