Abstract
Background
The effort-independent tidal breathing test used by oscillometry presents a viable alternative for following up patients whose condition is stable while they are receiving biologic therapy.
Objective
We aimed to determine intrasession and intersession repeatability values for airwave oscillometry (AOS) and spirometry in patients who were already taking benralizumab.
Methods
In all, 21 patients with severe eosinophilic asthma attended the Scottish Centre for Respiratory Research as part of a clinical trial (EudraCT identification number 2019-003763-22). Paired AOS and spirometry values were obtained at 3 separate visits (baseline and days 28 and 56) with no change in asthma therapy.
Results
Intrasession agreement between repeated measurements for AOS and spirometry was excellent (intraclass correlation coefficient ≥ 0.90) at all 3 visits. Intersession agreement was also excellent (intraclass correlation coefficient ≥ 0.80).
Conclusion
In this study we report medium-term intrasession and intersession repeatability values for airwave oscillometry and spirometry in a cohort of severely asthmatic patients receiving benralizumab therapy. Oscillometry can be used to follow up patients with asthma who are taking biologics.
Key words: Benralizumab, asthma, airway oscillometry, repeatability
Introduction
Following published evidence from phase 3 clinical trials supporting the use of biologics in carefully selected patients with uncontrolled severe asthma,1 emphasis has been placed on monitoring patients whose condition remains stable while they are receiving biologic therapy. Conventional spirometry has advantages, including widely accepted reference values and excellent repeatability in clinical trials.2 However, a real-life clinical study has recently shown that only a small proportion of spirometry tests currently fulfil the American Thoracic Society/European Respiratory Society (ERS) criteria in routine practice.3 In our clinical experience however, spirometry relies on an effort-dependent forced expiratory maneuver with which some severely asthmatic patients struggle to cope. In contrast, the effort-independent tidal breathing test used by oscillometry presents a viable alternative for assessing lung resistance and reactance when following up patients whose condition remains stable while they are receiving biologic therapy. We therefore hypothesize that oscillometry is a useful alternative to spirometry when measuring stable lung function in patients with severe asthma who are receiving biologic therapies. We aimed to determine intrasession and intersession repeatability values for airwave oscillometry (AOS) and spirometry in patients who were already taking benralizumab.
Results and discussion
In all, 21 patients with severe eosinophilic asthma attended the Scottish Centre for Respiratory Research as part of a clinical trial (EudraCT number 2019-003763-22). AOS was measured in triplicate by experienced operators using Tremoflo (Thorasys, Montreal, Quebec, Canada) in accordance with ERS technical standards before any spirometry maneuvers.4 Patients were instructed to maintain an upright posture with a slightly uplifted chin, provide cheek support with their hands, and utilize nose clips throughout the procedure. Between 3 and 8 measurements, each performed during 20 seconds of tidal breathing, were obtained with the 3 values deemed most free of visible tracing artefacts averaged. The AOS device was calibrated daily by using a resistance load of 0.2 kPa/L per second. Spirometry (Micromedical, Chatham, UK) was performed according to ERS/American Thoracic Society guidelines with the best of 3 values taken.5 Paired AOS and spirometry values were obtained at 3 separate visits (at baseline and on days 28 and 56) with no change in asthma therapy.
All patients had already been taking benralizumab for 4 weeks at baseline, with efficacy confirmed by near-complete depletion of peripheral blood eosinophils (13 cells/μL). Statistical analyses were performed by using SPSS, version 27 (IBM, Armonk, NY), with a 2-tailed α-error set at 0.05. Coefficients of variation (CVs) were determined by dividing the SD of the sample by the sample mean. Intraclass correlation coefficients (CCs) were calculated for the triplicate baseline measurements of all visits (intrasession), and interclass CCs were calculated for the means of these triplicate measurements (intersession) by using a 2-way mixed model with absolute agreement. Intraclass and interclass CCs were deemed excellent if greater than 0.80.6 Ethical approval was obtained from East of Scotland Research Ethics Committee before all data collection. A repeated measures ANOVA was used to assess any time-dependent effects between visits, followed by Bonferroni-corrected pairwise testing.
The mean baseline demographic values were as follows: ratio of females to males, 9 to 12; mean age, 53 years; mean body mass index, 30 kg/m2; percentage of patients taking a long-acting β-agonist, 95%; percentage of patients taking a long-acting muscarinic antagonist, 57%; percentage of patients taking a leukotriene receptor antagonist 62%; percentage of patients taking theophylline, 14%; mean inhaled corticosteroid beclomethasone dipropionate equivalent dose, 1895 μg; percentage of ex-smokers, 38%; mean FEV1 value, 80%; mean forced expiratory flow value between 25% and 75% of forced vital capacity (FEF25-75), 42%; mean forced vital capacity value, 100%; resistance at 5 Hz (R5), 161%.
Table I depicts the mean values and intrasession CVs for AOS and spirometry measurements at baseline, day 28, and day 56, and Table II presents the respective intersession CVs and intersession CCs. Except for the FEF25-75 values between baseline and day 28 and those between baseline and day 56, there were no other statistically significant time differences between the mean values, intrasession CVs, or intersession CVs. Although CVs varied, the levels of intrasession agreement between repeated measurements for AOS and spirometry were excellent (intrasession CC ≥ 0.90) at all 3 visits (Table I). The levels of intersession agreements were also excellent (intersession CC ≥ 0.80) despite the differences in CVs (Table II).
Table I.
Intrasession CVs and intraclass CCs for airwave oscillometry and spirometry results
| Indicator | Baseline |
Day 28 |
Day 56 |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Mean (95% CI) | CV (95% CI) | Intrasession CC (95% CI) | Mean (95% CI) | CV (95% CI) | Intrasession CC (95% CI) | Mean (95% CI) | CV (95% CI) | Intrasession CC (95% CI) | |
| R5 (kPa/L per s) | 0.51 (0.42, 0.60) | 5.2% (3.1, 7.2) | 0.98 (0.97, 0.99) | 0.50 (0.43-0.58) | 7.3% (4.4-10.2) | 0.97 (0.93, 0.99) | 0.50 (0.41-0.60) | 5.9% (4.5-7.3) | 0.99 (0.98, 1.00) |
| R20 (kPa/L per s) | 0.36 (0.31, 0.41) | 6.1% (4.5, 7.8) | 0.97 (0.94, 0.99) | 0.36 (0.33-0.40) | 7.3% (4.4-10.2) | 0.91 (0.82, 0.96) | 0.36 (0.32-0.40) | 4.7% (3.5-6.0) | 0.98 (0.96-0.99) |
| R5–R20 (kPa/L per s) | 0.16 (0.09-0.22) | 24.3% (16.1-32.6) | 0.98 (0.96, 0.99) | 0.14 (0.08-0.20) | 36.1% (4.5-67.8) | 0.98 (0.97-0.99) | 0.15 (0.08-0.22) | 26.1% (14.6-37.6) | 0.99 (0.98-1.00) |
| AX (kPa/L) | 2.34 (1.22-3.46) | 14.4% (10.9-17.9) | 0.98 (0.96-0.99) | 2.49 (1.39-3.59) | 17.7% (12.5-22.9) | 0.99 (0.98-1.00) | 2.30 (1.07-3.54) | 18.5% (11.5-25.5) | 0.99 (0.98-1.00) |
| Fres (Hz) | 23.06 (19.81-26.30) | 5.7% (3.2-8.2) | 0.98 (0.95-0.99) | 24.06 (20.24-27.88) | 7.0% (4.4-9.7) | 0.98 (0.96-0.99) | 22.14 (19.06-25.21) | 9.8% (6.0-13.6) | 0.95 (0.90-0.98) |
| FEV1 (L) | 2.42 (2.03-2.82) | 3.3% (2.2-4.3) | 1.00 (0.99-1.00) | 2.42 (2.09-2.76) | 3.2% (1.7-4.6) | 1.00 (0.99-1.00) | 2.42 (2.10-2.74) | 3.3% (2.0-4.7) | 0.99 (0.99-1.00) |
| FEF25-75 (L/s) | 1.54 (1.19-1.89) | 7.6% (5.6-9.6) | 0.98 (0.97-0.99) | 1.49 (1.21-1.78) | 7.1% (4.1-10.0) | 0.99 (0.98-1.00) | 1.52 (1.25-1.79) | 8.5% (6.1-10.9) | 0.98 (0.97-0.99) |
| FVC (L) | 3.68 (3.09-4.27) | 3.0% (1.9-4.1) | 1.00 (0.99-1.00) | 3.70 (3.15-4.25) | 3.0% (1.5-4.5) | 1.00 (0.99-1.00) | 3.68 (3.13-4.24) | 2.9% (1.8-4.0) | 1.00 (0.99-1.00) |
Fres, Resonant frequency; FVC, forced vital capacity; R5–R20, difference in resistance between R5 and R20.
Table II.
Intersession CVs and intraclass CCs for airwave oscillometry and spirometry results
| Indicator | Baseline to day 28 |
Day 28 to day 56 |
Baseline to day 56 |
|||
|---|---|---|---|---|---|---|
| CV (95% CI) | Intersession CC (95% CI) | CV (95% CI) | Intersession CC (95% CI) | CV (95% CI) | Intersession CC (95% CI) | |
| R5 (kPa/L per s) | 10.8% (6.1-15.6) | 0.89 (0.72-0.95) | 13.2% (8.9-17.5) | 0.89 (0.73-0.96) | 14.2% (8.0-20.5) | 0.88 (0.71-0.95) |
| R20 (kPa/L per s) | 6.0% (2.6-9.4) | 0.92 (0.80-0.97) | 7.0% (5.2-8.8) | 0.92 (0.81-0.97) | 9.1% (5.6-12.5) | 0.90 (0.74-0.96) |
| R5–R20 (kPa/L per s) | 33.7% (20.6-46.8) | 0.90 (0.74-0.96) | 36.5% (25.7-47.2) | 0.92 (0.79-0.97) | 38.4% (22.0-54.7) | 0.95 (0.86-0.98) |
| AX (kPa/L) | 26.3% (14.9-37.8) | 0.92 (0.80-0.97) | 36.2% (24.0-48.5) | 0.90 (0.75-0.96) | 37.3% (25.5-49.1) | 0.91 (0.77-0.96) |
| Fres (Hz) | 10.5% (6.1-15.0) | 0.89 (0.72-0.96) | 13.9% (9.1-18.8) | 0.86 (0.65-0.94) | 15.0% (8.9-21.1) | 0.79 (0.41-0.92) |
| FEV1 (L) | 4.2% (1.6-6.8) | 0.97 (0.93-0.99) | 4.5% (3.1-5.9) | 0.98 (0.95-0.99) | 6.7% (4.1-9.3) | 0.94 (0.85-0.98) |
| FEF25-75 (L/s) | 10.6% (5.4-15.8)∗ | 0.94 (0.85-0.98) | 7.7% (5.4-10.1) | 0.96 (0.91-0.98) | 14.5% (9.5-19.5) ∗ | 0.89 (0.72-0.95) |
| FVC (L) | 3.5% (2.2-4.8) | 0.99 (0.98-1.00) | 3.6% (2.1-5.1) | 0.99 (0.97-1.00) | 3.9% (2.4-5.4) | 0.99 (0.96-0.99) |
Fres, Resonant frequency; FVC, forced vital capacity; R5–R20, difference in resistance between R5 and R20.
P < .05.
In this study we have reported medium-term intrasession and intersession repeatability values for AOS and spirometry in a cohort of severely asthmatic patients who were already undergoing benralizumab therapy. Notably, the mean intrasession CVs for R5 were well within the range of 10% or less, which is in keeping with the current ERS technical standards.4 Although the intrasession CVs varied between 4.7% and 36.1% for the variables R5, resistance at 20 Hz (R20), the difference in resistance between R5 and R20, area under the reactance curve (AX), and resonant frequency, all of the intrasession CCs exceeded 0.90, for excellent agreement between individual measurements. All intrasession spirometry measurements exhibited low variability (CV < 10%) and high repeatability (intrasession CC ≥ 0.90). As to be expected in keeping with the findings of a previous study,7 intersession repeatability for AOS and spirometry decreased with longer duration between visits. However, with the exception of resonant frequency, all AOS and spirometry measurements once again demonstrated excellent repeatability (intersession CC ≥ 0.85) between visits.
The authors of a previous study found that impulse oscillometry resistance measurements had the potential for detecting bronchodilation in healthy individuals but was limited by greater variability.8 Here, we have validated these findings of greater variability in a cohort of severely asthmatic patients but have also demonstrated high repeatability, albeit by measuring airway resistance and reactance using a different device. Ultimately, oscillometry mimics lung physiology more closely than spirometry because patients would not usually perform a forced expiratory maneuver in real life.
The results from this study using AOS are comparable to those from a recent study looking at repeatability in patients with severe asthma, which used 2 measurements of impulse oscillometry (IOS) over approximately 1 year.9 Although the intersession CVs were relatively high for the difference in resistance between R5 and R20 (38.4%) and AX (37.3%), the intersession CCs remained high, with all parameters exceeding 0.90. Additionally, the levels of intrasession and intersession repeatability for spirometry measurements were all excellent (intrasession CC and intrasession CC ≥ 0.85) with low variability (CV < 15%). Pointedly, the mean changes in AOS and spirometry parameters did not exceed the previously reported biologic variability values between visits, providing further evidence that pulmonary function remained stable during this follow-up period.9
Although the findings from the present study support oscillometry as a consistent measurement technique, the strong intersession CCs might equally indicate insensitivity to changes in lung function. However, we believe that this is highly unlikely, as it has previously been shown that standardized response means for oscillometry bronchodilator responses are equally as sensitive as FEV1 value in patients with severe asthma.10
We appreciate the limitations of this study, including the relatively small sample size, which perhaps might be somewhat mitigated by multiple repeated measures over 3 separate study visits. Additionally, we included a cohort of patients undergoing biologic therapy who experienced no change in their asthma therapy or pulmonary function for the entire study duration. Although our patients had preserved FEV1 values, there was evidence of small airway dysfunction at baseline for spirometry (FEF25-75 value, 42%) and oscillometry (difference between R5 and R20, 0.16 kPa/L per second; AX, 2.34 kPa/L). In conclusion, although airwave oscillometry demonstrated higher variability than spirometry, as measured by CVs, repeatability was high for both measurements of pulmonary function.
Disclosure statement
Disclosure of potential conflict of interest: R. Chan reports personal fees (for talks) and support (for attending ERS 2022) from AstraZeneca; personal fees (for consulting) from Vitalograph; and personal fees (for talks) from Thorasys. B. Lipworth reports nonfinancial support (equipment) from GSK; grants, personal fees (for consulting, talks, and advisory board participation), and other support (for attending American Thoracic Society and ERS events) from AstraZeneca; grants, personal fees (for consulting, talks, and advisory board participation) and other support (for attending ERS events) from Teva; personal fees (for consulting) from Sanofi; personal fees (for consulting, talks, and advisory board participation) from Circassia; personal fees from Thorasys (for consulting and talks) in relation to the submitted work; personal fees (for consulting) from Lupin; personal fees (for consulting) from Glenmark; personal fees (for consulting) from Dr Reddy, personal fees (for consulting) from Sandoz; grants, personal fees (for consulting, talks, and advisory board participation), and other support (for attending a British Thoracic Society event) from Boehringer Ingelheim; and grants and personal fees (for advisory board participation and talks) from Mylan outside the submitted work. B. Lipworth's son is presently an employee of AstraZeneca.
Clinical implications.
In this study we report medium-term intrasession and intersession repeatability values for AOS and spirometry in a cohort of severely asthmatic patients receiving benralizumab therapy. Oscillometry can be used to follow up patients with asthma who are taking biologics.
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