Abstract
Fractional exhaled nitric oxide (FENO) demonstrates marked same-day variation in patients with severe asthma, which may impact on clinical decisions. The same-day variability must be carefully considered when interpreting FENO as a single-breath test. https://bit.ly/38M1eJV
To the Editor:
Fractional exhaled nitric oxide (FENO) is a single-breath test used in asthma diagnosis and management. Whilst a number of studies in mild to moderate asthma have demonstrated excellent repeatability of FENO by assessing intra-device reproducibility from consecutive blows [1–3], the reported between-session and diurnal variability have been inconsistent [4–9]. Asthma is a highly variable disease. The excessive diurnal variability in airflow obstruction is a marker for disease severity, poor control and mortality. Diurnal variability of FENO is also a predictor for poor asthma control [8]. We have demonstrated that FENO has a significant time-of-the-day difference with a median of 12 ppb between peak and trough readings within a 24-h cycle in stable mild/moderate asthma [10]; whether this same-day variation is clinically significant in the diagnosis and management of asthma remains unclear. FENO has been readily used in the monitoring of severe asthma, but its same-day reproducibility as a single-breath test is unknown in this group.
We investigated the same-day reproducibility of FENO as a single-breath test in patients with severe asthma.
Participants were recruited via Manchester Allergy, Respiratory and Thoracic Surgery Biobank (REC 15/NW/0409). Clinical data were recorded and baseline FENO measured (NIOX Vero; Aerocrine, Solna, Sweden) with a single blow between 08:00 and 09:00 h, before inhaled corticosteroids and other regular medications were administered under direct supervision. FENO measurements were then repeated at 1, 2, 4 and 8 h. Spirometry was performed after each FENO measurement. Food was provided at standard times by the hospital catering service. All study participants gave written informed consent.
Mean FENO (FENOmean) was defined as the mean of repeated measurements within the same subject. The intra-subject maximum difference (FENOmax_diff) was defined as the difference between the highest and lowest FENO value for each individual. FENOvariability was calculated by the formula: FENOmax_diff/FENOmean and was presented as a percentage value.
Summary data are presented as median (interquartile range; IQR). Pearson's correlation (with bootstrapping) was used for comparisons of measurements (IBM SPSS 20). Missing data were excluded.
A total of 43 patients (age 50 (44–59) years, 25.6% male, two current smokers) completed the study. All participants were on British Thoracic Society step 4/5 treatment, with 30 (69.8%) on maintenance systemic corticosteroids and 27 (62.8%) on biological therapies for asthma. The majority (93%) had features of allergic sensitisation and/or serum/sputum eosinophilia. The median (IQR) daily dose of inhaled corticosteroids was 2000 (1600–2000) μg beclometasone dipropionate equivalent, with 75.0% (58.0–100.0%) adherence based on general practitioner prescription records. Participants had median (IQR) 1 (1–3) asthma exacerbations within the past 12 months, and 28 (65.1%) participants had previous admission to intensive care unit due to asthma. No participants had an acute exacerbation during the study period. The baseline forced expiratory volume within 1 s (FEV1) was 59.5% (50.0–73.3%) of predicted.
11 FENO measurements were missing (all at the 8-h time-point), leaving 204 readings included in the analysis. The median (IQR) FENOmean was 23.5 (12.8–47.4) ppb. Age, sex, use of biologics and oral corticosteroids, exacerbation rates and medication compliance were not significantly associated with FENOmean.
FENO measurements at baseline were lower than those measured around midday (at 2-h and 4-h time points, with mean±sd difference of −3.7±7.9 ppb and −3.4±8.2 ppb; p<0.01). There was no significant difference in FENO before and after meals. The median (IQR) FENOmax_diff was 10.0 (4.0–15.0) ppb and FENOvariability was 29.2% (17.9–54.7%). FENOmax_diff was correlated with FENOmean (r=0.81, p<0.001) (figure 1), but not FENOvariability (p=0.19). FENOmean was not correlated with FENOvariability (p=0.29). Patient demographics, use of medication and lung function were not significantly associated with FENOvariability or FENOmax_diff.
Same-day repeatability of fractional exhaled nitric oxide (FENO) in patients with severe asthma. a) The differences between individual FENO measurements taken at different time-points and mean FENO. b) Same-day FENOmax_diff increases with mean FENO. c) A significant proportion of patients had FENO variability of >20% within the same day.
In participants who had a FENOmean of 50 ppb or more (n=10), the median (IQR) FENOmax_diff was 22.5 (14.3–55.3) ppb and FENOvariability 21.9% (18.7–33.1%). In those who had FENOmean of less than 50 ppb, the median (IQR) FENOmax_diff was 6.0 (3.0–11.5) ppb and FENOvariability 33.1% (15.5–56.7%). 10 (23.3%) patients had FENO measurements that straddled 25 ppb or 50 ppb cut-off points within the same day.
FENOmean did not show significant correlation to FEV1 % predicted (p=0.31). The median (IQR) of FEV1 % predicted maximum difference was 5.0% (2.0–13.0%) and FEV1 % predicted variability (defined as (maximum−minimum)/mean FEV1 % predicted) 8.7% (3.8–20.6%). Same-day variability in FENO was significantly greater than FEV1 variability (p<0.001), but there was no significant correlation between the two (p=0.16).
We have shown that within-day variability of FENO in severe asthma is significant and clinically relevant. Consistent with this, Saito et al. [8] had also demonstrated a similar amplitude of diurnal variation in FENO in patients with severe asthma, although that was not using a currently approved single-breath method. In our study, we measured FENO during clinical hours (between 08:00 h and 17:00 h) when the test is most commonly performed in the outpatient clinical setting in primary or secondary care. Whilst FENO measurements out of working hours may be useful in asthma management [8], they are not currently approved for home-based testing; indeed before this could happen further study would be required to describe variability over such extended time periods.
Whilst diurnal variation in lung function and FENO are both predictive of poor asthma control [8, 11, 12], we did not demonstrate any significant correlation between these in our study. Saito et al. [8] had previously demonstrated increased diurnal variability in FENO in uncontrolled asthmatics compared to those with well-controlled asthma, but no significant differences in the diurnal variability in peak flow. This may suggest that same-day variation in FENO is a more sensitive predictor for asthma control than lung function.
We note that a marginal reduction in FENO levels following spirometry manoeuvres has been reported, although not consistently [13, 14]. Nevertheless, the reduction in FENO returns to baseline within 1 h [13]. In our study, FENO was performed prior to spirometry at each time point, leaving a minimum of a 1-h gap between previous spirometry and FENO measurements.
There is a paucity of data to suggest what constitutes a minimal clinically important difference (MCID) in FENO, and the significant same-day variability adds further challenge to this. The most recent recommendations made by the American Thoracic Society (ATS) are now almost a decade old and the suggested MCID was based only on expert opinion [15]. A fall of >20% in FENO for values over 50 ppb, or 10 ppb for FENO less than 50 ppb, from one visit to the next were said to indicate treatment response [15]. Our study highlights that this suggested MCID and clinically relevant cut-off values in FENO must be considered with caution. Strikingly, 70% of those with a FENO more than 50 ppb and a third of those with FENO of less than 50 ppb in our study had met ATS-defined MCID in FENO within the same day. Further, almost a quarter of patients had FENO that straddled ATS-defined clinically relevant cut-off points (25 ppb and 50 ppb) within the same day, leading to potential misinterpretation in a significant proportion of patients. In the current study, we have demonstrated that a FENOmean of 30 ppb has a same-day variability of 10 ppb (figure 1). More recently, Heaney et al. [16] have demonstrated that a suppression of FENO by at least twice as much as suggested by the ATS guideline (−42% or more) in severe asthma patients with high FENO (≥45 ppb) was associated with a significant improvement in both lung function and asthma control following treatment. This improvement was not observed in those who failed to reach the minimum FENO suppression (−42%), indicating that the MCID for positive treatment response may be much higher than previously suggested [15]. With the increasing use of FENO in the management of asthma, urgent research is needed to determine the MCID of FENO as a single-breath test, and the significant same-day, between-session variability of FENO must be carefully considered.
FENO demonstrates significant same-day variation in patients with severe asthma. This variation will have an impact on clinical decisions in some patients. Further studies are urgently needed to confirm the time-of-day effect of FENO and the impact on clinical use and interpretation of FENO in severe asthma.
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Supplementary Material
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Acknowledgement
We would like to thank the staff of the severe asthma team for assistance with participant recruitment and data collection.
Footnotes
Conflict of interest: F. Alahmadi has nothing to disclose.
Conflict of interest: R. Niven has nothing to disclose.
Conflict of interest: S.J. Fowler has nothing to disclose.
Conflict of interest: R. Wang has nothing to disclose.
Support statement: R. Wang and S.J. Fowler are supported by the NIHR Manchester Biomedical Research Centre. We acknowledge the support of the NIHR Manchester Clinical Research Facility, Manchester Allergy, Respiratory and Thoracic Surgery (ManARTS) Biobank and the North West Lung Centre Charity in carrying out this study.
- Received September 4, 2020.
- Accepted January 11, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org