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Using fractional exhaled nitric oxide to guide step-down treatment decisions in asthma: practical considerations

Kay Wang, Jan Y. Verbakel, Jason Oke, Alexander Fleming-Nouri, Norihiro Harada, Ryo Atsuta, Tomoyuki Fujisawa, Tomotaka Kawayama, Hiromasa Inoue, Stephen Lazarus, Stanley Szefler, Fernando D. Martinez, Dominick Shaw, Ian D. Pavord, Mike Thomas
European Respiratory Journal 2020 56: 2002809; DOI: 10.1183/13993003.02809-2020
Kay Wang
1Nuffield Dept of Primary Care Health Sciences, University of Oxford, Oxford, UK
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  • For correspondence: kay.wang@phc.ox.ac.uk
Jan Y. Verbakel
2KU Leuven, Dept of Public Health and Primary Care, Leuven, Belgium
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Jason Oke
1Nuffield Dept of Primary Care Health Sciences, University of Oxford, Oxford, UK
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Alexander Fleming-Nouri
3Oxford University Clinical Academic Graduate School, University of Oxford, Oxford, UK
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Norihiro Harada
4Dept of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan
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Ryo Atsuta
4Dept of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan
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Tomoyuki Fujisawa
5Second Division Dept of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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  • ORCID record for Tomoyuki Fujisawa
Tomotaka Kawayama
6Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Kurume, Japan
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Hiromasa Inoue
7Dept of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Stephen Lazarus
8Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA, USA
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Stanley Szefler
9Children's Hospital Colorado, The Breathing Institute, Dept of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
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Fernando D. Martinez
10Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA
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Dominick Shaw
11Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, UK
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Ian D. Pavord
12Nuffield Dept of Medicine, University of Oxford, Oxford, UK
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Mike Thomas
13Primary Care, Population Sciences and Medical Education (PPM), University of Southampton, Southampton, UK
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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
https://www.ersjournals.com/user-licence

References

  1. ↵
    1. Wang K,
    2. Verbakel JY,
    3. Oke J, et al.
    Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis. Eur Respir J 2020; 55: 1902150. doi:10.1183/13993003.02150-2019
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Pérez de Llano L,
    2. García-Rivero JL,
    3. Urrutia I, et al.
    A simple score for future risk prediction in patients with controlled asthma who undergo a guidelines-based step-down strategy. J Allergy Clin Immunol Pract 2019; 7: 1214–1221. doi:10.1016/j.jaip.2018.10.017
    OpenUrl
  3. ↵
    1. Lehtimaki L,
    2. Csonka P,
    3. Makinen E, et al.
    Predictive value of exhaled nitric oxide in the management of asthma: a systematic review. Eur Respir J 2016; 48: 706–714. doi:10.1183/13993003.00699-2016
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Berry MA,
    2. Shaw DE,
    3. Green RH, et al.
    The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy 2005; 35: 1175–1179. doi:10.1111/j.1365-2222.2005.02314.x
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Harada S,
    2. Harada N,
    3. Itoigawa Y, et al.
    Evaluation of switching low-dose inhaled corticosteroid to pranlukast for step-down therapy in well-controlled patients with mild persistent asthma. J Asthma 2016; 53: 207–212. doi:10.3109/02770903.2015.1087556
    OpenUrl
  6. ↵
    1. Lazarus SC,
    2. Boushey HA,
    3. Fahy JV, et al.
    Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285: 2583–2593. doi:10.1001/jama.285.20.2583
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Pauwels RA,
    2. Löfdahl CG,
    3. Postma DS, et al.
    Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405–1411. doi:10.1056/NEJM199711133372001
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Lloyd A,
    2. Price D,
    3. Brown R
    . The impact of asthma exacerbations on health-related quality of life in moderate to severe asthma patients in the UK. Prim Care Respir J 2007; 16: 22–27. doi:10.3132/pcrj.2007.00002
    OpenUrlCrossRefPubMed
  9. ↵
    1. Lee LK,
    2. Obi E,
    3. Paknis B, et al.
    Asthma control and disease burden in patients with asthma and allergic comorbidities. J Asthma 2018; 55: 208–219. doi:10.1080/02770903.2017.1316394
    OpenUrl
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Using fractional exhaled nitric oxide to guide step-down treatment decisions in asthma: practical considerations
Kay Wang, Jan Y. Verbakel, Jason Oke, Alexander Fleming-Nouri, Norihiro Harada, Ryo Atsuta, Tomoyuki Fujisawa, Tomotaka Kawayama, Hiromasa Inoue, Stephen Lazarus, Stanley Szefler, Fernando D. Martinez, Dominick Shaw, Ian D. Pavord, Mike Thomas
European Respiratory Journal Aug 2020, 56 (2) 2002809; DOI: 10.1183/13993003.02809-2020

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Using fractional exhaled nitric oxide to guide step-down treatment decisions in asthma: practical considerations
Kay Wang, Jan Y. Verbakel, Jason Oke, Alexander Fleming-Nouri, Norihiro Harada, Ryo Atsuta, Tomoyuki Fujisawa, Tomotaka Kawayama, Hiromasa Inoue, Stephen Lazarus, Stanley Szefler, Fernando D. Martinez, Dominick Shaw, Ian D. Pavord, Mike Thomas
European Respiratory Journal Aug 2020, 56 (2) 2002809; DOI: 10.1183/13993003.02809-2020
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