Abstract
Using FENO to guide safe step-down treatment decisions in patients with well-controlled asthma should involve gradual, carefully monitored reductions and consider other potential risk factors for acute exacerbations https://bit.ly/2E2W679
From the authors:
We thank L. Pérez de Llano and colleagues for their comments on our study [1] and for comparing our findings with those of their prospective multicentre study describing a simple score for predicting step-down failure in adults with well-controlled asthma [2]. However, we would like to clarify that recent systematic review findings conclude that there is insufficient evidence, rather than evidence against, the ability of low fractional exhaled nitric oxide (FENO) to identify individuals in whom treatment can be safely stepped down [3].
We fully acknowledge that FENO should be interpreted in the context of other potential risk factors and that pro-active efforts should be made to identify and treat other conditions that increase FENO, particularly in patients whose FENO is high despite satisfactory medication adherence and inhaler technique.
We also acknowledge that, although there is well-established evidence that FENO is correlated with sputum eosinophil counts in nonsmoking patients with stable asthma [4], this correlation is not strong and it is possible for eosinophilic airway inflammation to occur in the presence of low FENO. However, it is neither feasible nor acceptable to obtain induced sputum samples in primary care. Blood eosinophil counts may be an adequate surrogate but this has not been demonstrated. We therefore recommend that, in community-based healthcare settings, treatment should be stepped down gradually and patients should be monitored carefully in case any reductions subsequently unmask undetected airway inflammation.
We are aware of the practical implications of variability in FENO measurements between different devices. However, this is unlikely to have had an undue impact on the findings of our meta-analysis, as only two included studies used Sievers rather than Aerocrine analysers [5, 6] and only three participants across these two studies had one or more exacerbations.
The study by L. Pérez de Llano and colleagues also highlights other issues that should be considered when using FENO to guide step-down decisions.
1) The definition of step-down failure. The primary outcome used by L. Pérez de Llano and colleagues was “loss of control”. This was defined as an Asthma Control Test score of ≤19, a decrease in forced expiratory volume in 1 s of ≥20% from baseline, or exacerbations resulting in symptom deterioration, whether or not these required treatment with systemic corticosteroids or hospitalisation. However, the primary outcome of our meta-analysis was exacerbations requiring antibiotics, systemic corticosteroids, hospitalisation or unscheduled healthcare visits. These events may relate more closely to type-2 airway inflammation than less severe events [7] and have a significant detrimental impact on health-related quality of life [8], which is in turn associated with increased asthma-related costs and healthcare resource utilisation [9]. Only ∼13% of participants who experienced loss of control in the study by L. Pérez de Llano and colleagues required systemic corticosteroids (13 out of 102 participants) and no participants were hospitalised. This would suggest that, while FENO may not be a reliable predictor of mild-to-moderate deteriorations in symptom control or lung function, it could still be a useful predictor of clinically important exacerbations requiring further intervention.
2) Target population characteristics. The list of possible diagnostic criteria for asthma used by L. Pérez de Llano and colleagues included FENO >50 ppb. However, none of the studies we included in our meta-analysis selected participants based on their FENO measurement at baseline. FENO may therefore have a greater predictive value in asthma populations that do not include individuals who have been pre-selected on the basis of already having a high FENO.
3) Follow-up after stepping down treatment. Whilst our meta-analysis only analysed one step-down episode per participant, L. Pérez de Llano and colleagues analysed all step-down episodes. Each participant could undergo up to three step-down episodes over a 12-month period, with a 6-month follow-up period after the step-down episode at the third study visit. However, analysis of multiple episodes per participant is likely to result in clustering of outcomes within individuals. Additionally, extended follow-up periods may result in exacerbations or “loss of control” episodes unrelated to treatment being stepped down.
In conclusion, we agree with L. Pérez de Llano and colleagues that FENO should not be considered in isolation to guide step-down treatment decisions. However, in real life clinical practice, it is practically impossible to control for every potential source of confounding or variability. We therefore advocate using FENO as part of a gradual, safely monitored step-down approach.
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Footnotes
Conflict of interest: K. Wang reports grants from National Institute for Health Research, during the conduct of the study.
Conflict of interest: J.Y. Verbakel has nothing to disclose.
Conflict of interest: J. Oke has nothing to disclose.
Conflict of interest: A. Fleming-Nouri has nothing to disclose.
Conflict of interest: N. Harada reports personal fees from AstraZeneca and GSK, outside the submitted work; and has a patent pending (Japanese Patent Application 2018-097070).
Conflict of interest: R. Atsuta has nothing to disclose.
Conflict of interest: T. Fujisawa has nothing to disclose.
Conflict of interest: T. Kawayama reports grants from Novartis, and personal fees from AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: H. Inoue reports grants from Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and personal fees from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Kyorin, Sanofi, outside the submitted work.
Conflict of interest: S. Lazarus reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NHLBI and American Lung Association - Airway Clinical Research Centers Network (ALA-ACRC), outside the submitted work.
Conflict of interest: S. Szefler reports other from Boehringer-Ingelheim, Genentech, GlaxoSmithKline, AstraZeneca, Daiichi Sankyo, Propeller Health, Sanofi and Regeneron, and grants from GlaxoSmithKline, outside the submitted work.
Conflict of interest: F.D. Martinez reports grants from NIH/NHLBI, NIH/NIEHS, NIH/NIAID, NIH/Office of Director, Johnson & Johnson, and personal fees from Copeval, outside the submitted work.
Conflict of interest: D. Shaw reports personal fees from AstraZeneca, GSK, TEVA, and Novartis, outside the submitted work.
Conflict of interest: I.D. Pavord reports personal fees from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, GlaxoSmithKline, Genentech and Regeneron; other funding from Teva, Chiesi, Sanofi, Circassia and Knopp, and grants from NIHR, outside the submitted work.
Conflict of interest: M. Thomas reports personal fees from GSK, Novartis and Boehringer Ingelheim, outside the submitted work; and recent membership of the BTS SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group.
- Received July 16, 2020.
- Accepted July 16, 2020.
- Copyright ©ERS 2020