Abstract
Background
While oscillometry appears advantageous over spirometry in detecting peripheral airway dysfunction, a feature of COPD, further research on its role in disease monitoring is needed. The objectives of the present study were to analyse the associations between oscillometry by impulse oscillometry (IOS) and forced oscillation technique (FOT) and airway obstruction, health status, dyspnoea and future exacerbations in COPD.
Methods
Oscillometry and disease burden were assessed in 150 adults with COPD within the Tools Identifying Exacerbations study. At 5 Hz, abnormal resistance (Rrs5) and reactance (Xrs5) were defined as z-scores >1.645 and <−1.645 sd, respectively, whereas a mean difference in reactance between inspiration and expiration >2.80 cmH2O·L−1·s−1 represented abnormal ΔXrs5. Forced expiratory volume in 1 s (FEV1), COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) scores were obtained. Medical records were reviewed for future exacerbations (≥1) between baseline and 1 and 3 years, respectively.
Results
Abnormal oscillometry correlated with disease burden, with the highest risk observed for severe airway obstruction (FEV1 <50% pred): odds ratios with 95% confidence intervals ranging from 4.80 (1.93–12.0) to 18.0 (7.13–45.3) for Rrs5, Xrs5 and ΔXrs5, followed by moderate to severe dyspnoea (mMRC ≥2) for ΔXrs5, COPD health status (CAT ≥10) for Rrs5 and ΔXrs5 and future exacerbations (1 and 3 years) for Rrs5 and Xrs5, respectively, with odds ratios (95% CI) ranging from 2.77 (1.27–6.05) to 3.98 (1.38–11.5).
Conclusions
Abnormal oscillometry may be relevant in the evaluation of COPD patients, including the prediction of future exacerbation risk.
Shareable abstract
Abnormal oscillometry relates to airway obstruction, health status, dyspnoea and future exacerbations in COPD. However, further studies are needed to investigate how oscillometry could be integrated in monitoring and risk assessment of COPD patients. https://bit.ly/42xHs11
Introduction
COPD is a lung condition [1] in which both genetics and environmental factors play important roles [2]. The disease is primarily characterised by progressive airway obstruction, but also gas trapping and diffusion impairment [3], associated with increased morbidity and mortality [4]. Common features include cough, sputum production and dyspnoea, but the symptom burden is highly variable depending on disease severity [4]. Thus, COPD is heterogeneous, both in its clinical features and underlying mechanisms, making disease management potentially challenging [3]. Airflow limitation, primarily assessed by the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC), remains central to the diagnosis [5]. Still, with varying functional impairments and subsequent symptomatology, spirometry alone has limitations in capturing the full complexity of the disease [3].
With peripheral airway obstruction being a silent signature of COPD, interest in lung function techniques sensitive to detecting changes in the small airways has increased [3]. One option is oscillometry, a noninvasive technique performed during spontaneous tidal breathing. The method may reflect breathing conditions in everyday life better than spirometry [6] and be more sensitive to detecting early changes in peripheral airway function [7]. By imposing mechanical oscillations at multiple frequencies (usually between 5 and 35 Hz) along the bronchial tree, techniques such as impulse oscillometry (IOS) and the forced oscillation technique (FOT) capture the mechanical properties of the respiratory system [7]. In brief, oscillometry assesses respiratory impedance (Zrs), encompassing both the resistance (Rrs) and reactance (Xrs) of the respiratory system. Rrs can be described as the pressure required to defy the resisting forces ahead of the applied sound wave and inflate the lungs, whereas Xrs reflects the lungs’ elastance and inertance, which depend on the stiffness of the lung and the chest wall and the mass of gas in the central airways, respectively [3, 6]. Lower frequencies travel further, reaching the smaller airways (<2 mm), and are thus considered to mirror the mechanical properties of the whole airway tree, whereas higher frequencies provide insight into the central parts [8].
In COPD, higher Rrs and lower Xrs have been reported, particularly at lower frequencies [9, 10]. In addition, higher Rrs and lower Xrs at 5 Hz have been linked to the severity of airflow limitation [11] and future exacerbations [12]. By calculating the within-breath change in Xrs at 5 Hz (ΔXrs5), oscillometry appeared advantageous over spirometry (FEV1) in detecting expiratory airflow limitation, a sign of dynamic hyperinflation often observed in COPD [6, 13]. Focusing on Rrs, Xrs and ΔXrs at 5 Hz, we aimed to study the associations between oscillometry and airway obstruction, health status, dyspnoea and future exacerbations in patients with COPD.
Methods
Study design
This observational study is based on information retrieved from the Tools Identifying Exacerbations (TIE) study, a prospective multidisciplinary study in Sweden [14]. Briefly, between 2014 and 2016, 571 COPD patients (International Classification of Disease codes J44.0, J44.1, J44.8 and J44.9) from primary and secondary care settings in central Sweden (Dalarna, Gävleborg and Uppsala) were enrolled. Inclusion criteria were spirometry-verified COPD diagnosis (post-bronchodilator FEV1/maximal vital capacity (VCmax) by FVC or slow vital capacity <0.70), age ≥40 years, ability to complete questionnaires and to partake in functional tests. Subjects with severe comorbidities were excluded. In addition to the extensive core protocol, IOS (n=132) and FOT (n=150) were performed in Uppsala.
The TIE study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the Regional Ethics Review Board in Uppsala, Sweden (2013/358). Informed written consent was collected from all participants at enrolment.
Study population
The study population consisted of 150 COPD patients with information on oscillometry (IOS or FOT), spirometry, health status and dyspnoea, at the inclusion visit, as well as future exacerbations between baseline and 3 years were included.
Data collection
Participants were investigated during a stable COPD state (no respiratory infections or exacerbations >4 weeks before the inclusion visit).
Background characteristics
At the inclusion visit, information on age, sex, comorbidities and smoking status was collected from a patient questionnaire. Height and weight were measured by trained healthcare professionals.
COPD health status and dyspnoea
The severity of COPD health status and dyspnoea were assessed at the inclusion visit, using the COPD Assessment Test (CAT) [15] and modified Medical Research Council (mMRC) [16] questionnaires. “Moderate to severe COPD health status” corresponded to a CAT score ≥10 [15]. “Moderate to severe dyspnoea” corresponded to an mMRC score ≥2 [16].
Exacerbations
All healthcare visits related to increased respiratory symptoms requiring treatment with bronchodilators/oral corticosteroids/antibiotics, referral to emergency department and/or hospitalisation due to COPD [17, 18] were classified as exacerbations. Information on exacerbations 1 year before inclusion was obtained from the patient questionnaire. Medical records were manually reviewed by healthcare professionals retrospectively, to collect information on the number of future exacerbations between baseline and 3 years. “Future exacerbations (1 year)” was defined as having ≥1 exacerbation between baseline and 1 year. “Future exacerbations (3 years)” was defined as having ≥1 exacerbation between baseline and 3 years. “Mean number of future exacerbations (3 years)” was defined as the summarised number of exacerbations between baseline and 3 years divided by 3 (years), categorised into three categories: 0, >0 and <1, and ≥1.
Lung function
Lung function by IOS, FOT and dynamic spirometry were performed 15 min after inhalation of bronchodilator (400 µg of salbutamol), with the participant breathing into a mouthpiece while sitting with head held in a neutral position, neck slightly extended, wearing a nose clip.
Following the European Respiratory Society (ERS) technical standards for oscillometry [7], IOS and FOT were performed during quiet tidal breathing using Jaeger MasterScreen IOS (CareFusion, Hoechberg, Germany) and Resmon Pro Full (Restech Srl, Milan, Italy) systems, respectively. Prior to the IOS test, calibration for volume (3.00 L) and resistance (0.20 kPa·L−1·s−1) was performed. The FOT system is factory-calibrated and auto-zeroed between each test. For both IOS and FOT measurements, participants were instructed to support their cheeks with both hands to prevent shunting of the applied pressure waves [7]. Whole breath measurements were performed over a minimum of 30 s and/or >5 breaths for IOS and >10 breaths for FOT, both tests were recorded in duplicates. With IOS reference values available only for Rrs5 and Xrs5 [19], the two parameters are presented consistently. Data on ΔXrs5 were available only for FOT. Due to limited access or technical failures, IOS was only measured in 132 participants, whereas all 150 participants performed FOT measurements.
After IOS and FOT were measured, dynamic spirometry was performed in accordance with the ERS standards [20] using the Jaeger MasterScreen PFT (CareFusion, Hoechberg, Germany). Before the test, the spirometer was calibrated for volume (3.00 L). Participants were instructed to breathe normally, inhale deeply and thereafter rapidly exhale as much air as possible for 15 s. The forced expiratory manoeuvres were recorded in sets of three.
“Severe airway obstruction” was defined as an FEV1 <50% pred [5]. “Abnormal IOS Rrs5 z-scores” [19] and “abnormal FOT Rrs5 z-scores” [9] were defined as values >1.645 sd [7]. “Abnormal IOS Xrs5 z-scores” [19] and “abnormal FOT Xrs5 z-scores” [9] were defined as values <−1.645 sd [7]. “Abnormal FOT ΔXrs5” was defined as a mean difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s−1 [13, 21].
Statistical analyses
Continuous variables are presented with medians and first (Q1) and third (Q3) quartiles and categorical variables with numbers (n) and percentages (%). Continuous and dichotomised IOS and FOT indices were compared by severity of airway obstruction, COPD health status, dyspnoea and future exacerbations (1 and 3 years), using the Mann–Whitney U test and the Chi2 test, respectively. Continuous and dichotomised IOS and FOT indices were compared across the categorised mean number of future exacerbations (3 years) using the Kruskal–Wallis H test. Associations between IOS or FOT indices and severity of airway obstruction, COPD health status, dyspnoea and future exacerbations (1 and 3 years) were examined in univariate and multivariate logistic regression models. Analyses for possible interactions of IOS or FOT indices and severe airway obstruction and asthma with the severity of COPD health status, dyspnoea and future exacerbations (1 and 3 years) were conducted (data not shown). All associations are presented with odds ratios and 95% confidence intervals. Sex, age, current smoking and exacerbations 1 year before the inclusion visit were treated as possible confounders. Statistical analyses were performed using Stata/IC 16.1 software. The statistical significance level was set at a two-tailed p-value <0.05.
Results
The study population consisted of 150 participants (61% women), 72% recruited from primary care settings, with a median (Q1, Q3) age of 68 (62, 71) years and body mass index of 26 (23, 29) kg·m−2 at the inclusion visit. In this study population, 29% were current smokers and 34% had ever been diagnosed with asthma. All participants had an FEV1/VCmax less than 0.70. Abnormal Rrs5 and Xrs5 by IOS were observed in 25% and 35%, with either of the two seen in 40%. The corresponding prevalences for FOT were 31% and 41%, collectively found in 47%. Abnormal ΔXrs5 by FOT was seen in 19%, of which 100% also had abnormal Rrs5 and/or Xrs5. Severe airway obstruction, moderate to severe COPD health status and dyspnoea were found in 32%, 69% and 47% of the participants, respectively. Additionally, 26% (1 year) and 49% (3 years) had experienced ≥1 future exacerbation (table 1).
TABLE 1.
Background characteristics, disease burden and lung function indices by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150) post salbutamol inhalation in the study population (n=150)
| Median (Q1, Q3) or n (%) | |
|---|---|
| Background characteristics | |
| Female | 91 (61) |
| Age, years | 68.0 (62.0, 71.0) |
| Body mass index, kg·m−2 | 26.0 (22.9, 29.4) |
| Exacerbations 1 year before inclusion visit | 39 (26) |
| Current smoker | 44 (29) |
| Current/previous asthma | 50 (34) |
| Primary care patient | 108 (72) |
| Disease burden | |
| FEV1, % pred | 61.0 (47.0, 75.0) |
| FVC, % pred | 69.5 (57.4, 81.5) |
| SVC, % pred | 77.1 (66.0, 90.4) |
| FEV1/VCmax | 0.52 (0.40, 0.61) |
| CAT score | 13.5 (9.00, 18.0) |
| mMRC score | 1.00 (1.00, 3.00) |
| Severe airway obstruction# | 48 (32) |
| Moderate/severe COPD health status¶ | 104 (69) |
| Moderate/severe dyspnoea+ | 70 (47) |
| Future exacerbations (1 year)§ | 39 (26) |
| Future exacerbations (3 years)§ | 73 (49) |
| Oscillometry indices | |
| IOS Rrs5 | |
| Z-score, continuous | 1.15 (0.78, 1.64) |
| Abnormal z-scoreƒ | 33 (25) |
| FOT Rrs5 | |
| Z-score, continuous | 0.86 (−0.06, 1.94) |
| Abnormal z-scoreƒ | 46 (31) |
| IOS Xrs5 | |
| Z-score, continuous | −1.03 (−2.03, −0.54) |
| Abnormal z-score## | 46 (35) |
| FOT Xrs5 | |
| Z-score, continuous | −0.94 (−4.35, 0.66) |
| Abnormal z-score## | 62 (41) |
| FOT ΔXrs5 | |
| Abnormal ΔXrs5¶¶ | 28 (19) |
Q1: first quartile (25th percentile); Q3: third quartile (75th percentile); SVC: slow vital capacity; VCmax: maximal vital capacity. #: defined as a forced expiratory volume in 1 s (FEV1) <50% pred. ¶: corresponded to a COPD Assessment Test (CAT) score ≥10. +: corresponded to a modified Medical Research Council (mMRC) dyspnoea score ≥2. §: defined as having ≥1 exacerbation between baseline and 1 and 3 years after the inclusion visit, respectively. ƒ: abnormal IOS resistance of the respiratory system at 5 Hz (Rrs5) z-scores [19] and abnormal FOT Rrs5 z-scores [9] were defined as values >1.645 sd. ##: abnormal IOS reactance of the respiratory system at 5 Hz (Xrs5) z-scores [19] and abnormal FOT Xrs5 z-scores [9] were defined as values <−1.645 sd. ¶¶: abnormal FOT ΔXrs5 was defined as a mean difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s¹.
Oscillometry indices by disease burden
Abnormal Rrs5 and Xrs5 were more common in severe airway obstruction (table 2). While moderate to severe COPD health status overall was observed in the presence of abnormal Rrs5 and Xrs5 by IOS and FOT, only participants with abnormal Xrs5 by FOT had higher rates of moderate to severe dyspnoea (table 3). When Rrs5 or Xrs5 by IOS and FOT were abnormal, the overall proportion of participants with future exacerbations (1 year) overall was larger. In contrast, future exacerbations (3 years) were only more frequent in participants with abnormal Rrs5 by FOT (table 4). Figure 1 shows the prevalence of severe airway obstruction, moderate to severe COPD health status and dyspnoea, and future exacerbations (1 and 3 years) among participants with both abnormal Rrs5 and Xrs5 by IOS (n=26) and FOT (n=38). In participants with abnormal ΔXrs5, severe airway obstruction, moderate to severe COPD health status and dyspnoea, and future exacerbations (1 year), were more common (tables 2–4).
TABLE 2.
Z-scores and abnormal z-scores for resistance of the respiratory system at 5 Hz (Rrs5), reactance of the respiratory system at 5 Hz (Xrs5) and mean difference in Xrs5 (ΔXrs5) by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150) post salbutamol inhalation by severity of airway obstruction
| Severe airway obstruction# | |||
|---|---|---|---|
| No (n=102)¶ | Yes (n=48)¶ | p-value+ | |
| Median (Q1, Q3) or n (%) | Median (Q1, Q3) or n (%) | ||
| IOS Rrs5 | |||
| Z-score, continuous | 1.05 (0.61, 1.32) | 1.52 (1.23, 2.02) | <0.001 |
| Abnormal z-score§ | 14 (16) | 19 (42) | 0.001 |
| FOT Rrs5 | |||
| Z-score, continuous | 0.34 (–0.59, 1.12) | 2.17 (1.29, 2.65) | <0.001 |
| Abnormal z-score§ | 15 (15) | 31 (65) | <0.001 |
| IOS Xrs5 | |||
| Z-score, continuous | –0.75 (−1.37, −0.44) | −2.08 (−2.58, −1.35) | <0.001 |
| Abnormal z-scoreƒ | 14 (16) | 32 (71) | <0.001 |
| FOT Xrs5 | |||
| Z-score, continuous | 0.14 (−1.22, 0.91) | −5.52 ( −7.91, −2.78) | <0.001 |
| Abnormal z-scoreƒ | 22 (22) | 40 (83) | <0.001 |
| FOT ΔXrs5 | |||
| Abnormal ΔXrs5## | 6 (6) | 22 (46) | <0.001 |
Q1: first quartile (25th percentile); Q3: third quartile (75th percentile).#: defined as a forced expiratory volume in 1 s <50% pred. ¶: numbers are given for participants with FOT measurements; the corresponding numbers for participants with IOS measurements are 87 for “no” and 45 for “yes”. +: Mann–Whitney U test or Chi2 test. §: abnormal IOS Rrs5 z-scores [19] and abnormal FOT Rrs5 z-scores [9] were defined as values >1.645 sd. ƒ: abnormal IOS Xrs5 z-scores [19] and abnormal FOT Xrs5 z-scores [9] were defined as values <−1.645 sd. ##: abnormal FOT ΔXrs5 was defined as a mean difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s−1.
TABLE 3.
Z-scores and abnormal z-scores for resistance of the respiratory system at 5 Hz (Rrs5), reactance of the respiratory system at 5 Hz (Xrs5) and mean difference in Xrs5 (ΔXrs5) by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150) post salbutamol inhalation by severity of COPD health status and dyspnoea
| Moderate/severe COPD health status# | |||
|---|---|---|---|
| No (n=46)¶ | Yes (n=104)¶ | p-value+ | |
| Median (Q1, Q3) or n (%) | Median (Q1, Q3) or n (%) | ||
| IOS Rrs5 | |||
| Z-score, continuous | 1.15 (0.89, 1.33) | 1.16 (0.75, 1.75) | 0.278 |
| Abnormal z-score§ | 5 (13) | 28 (30) | 0.029 |
| FOT Rrs5 | |||
| Z-score, continuous | 0.80 (−2.22, 1.68) | 0.88 (0.01, 2.17) | 0.571 |
| Abnormal z-score§ | 12 (26) | 32 (33) | 0.419 |
| IOS Xrs5 | |||
| Z-score, continuous | −0.77 (−1.46, −0.46) | −1.26 (−2.16, −0.66) | 0.014 |
| Abnormal z-scoreƒ | 9 (23) | 37 (40) | 0.005 |
| FOT Xrs5 | |||
| Z-score, continuous | −0.09 (−2.13, 0.75) | −1.32 (−5.52, 0.43) | 0.024 |
| Abnormal z-scoreƒ | 13 (28) | 49 (47) | 0.031 |
| FOT ΔXrs5 | |||
| Abnormal ΔXrs5## | 3 (7) | 25 (24) | 0.007 |
| Moderate/severe dyspnoea¶¶ | |||
|---|---|---|---|
| No (n=80)++ | Yes (n=70)++ | p-value+ | |
| Median (Q1, Q3) or n (%) | Median (Q1, Q3) or n (%) | ||
| IOS Rrs5 | |||
| Z-score, continuous | 1.15 (0.56, 1.62) | 1.16 (0.89, 1.68) | 0.225 |
| Abnormal z-score§ | 18 (24) | 15 (26) | 0.840 |
| FOT Rrs5 | |||
| Z-score, continuous | 0.77 (−0.53, 1.81) | 0.92 (0.18, 2.11) | 0.288 |
| Abnormal z-score§ | 26 (33) | 20 (29) | 0.603 |
| IOS Xrs5 | |||
| Z-score, continuous | −0.92 (−1.76, −0.49) | −1.20 (−2.56, −0.66) | 0.030 |
| Abnormal z-scoreƒ | 21 (28) | 25 (43) | 0.078 |
| FOT Xrs5 | |||
| Z-score, continuous | −0.54 (−2.67, 0.92) | −1.50 (−7.28, 0.40) | 0.001 |
| Abnormal z-scoreƒ | 27 (34) | 35 (50) | 0.044 |
| FOT ΔXrs5 | |||
| Abnormal ΔXrs5## | 6 (8) | 22 (31) | <0.001 |
Q1: first quartile (25th percentile); Q3: third quartile (75th percentile). #: corresponding to a COPD Assessment Test score ≥10. ¶: numbers are given for participants with FOT measurements; the corresponding numbers for participants with IOS measurements are 40 for “no” and 92 for “yes”. +: Mann–Whitney U test or Chi2 test. §: abnormal IOS Rrs5 z-scores [19] and abnormal FOT Rrs5 z-scores [9] were defined as values >1.645 sd. ƒ: abnormal IOS Xrs5 z-scores [19] and abnormal FOT Xrs5 z-scores [9] were defined as values <−1.645 sd. ##: abnormal FOT ΔXrs5 was defined as a mean difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s−1. ¶¶: corresponding to a modified Medical Research Council dyspnoea score ≥2. ++: numbers are given for participants with FOT measurements; the corresponding numbers for participants with IOS measurements are 74 for “no” and 58 for “yes”.
TABLE 4.
Z-scores and abnormal z-scores for resistance of the respiratory system at 5 Hz (Rrs5), reactance of the respiratory system at 5 Hz (Xrs5) and mean difference in Xrs5 (ΔXrs5) by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150) post salbutamol inhalation by future exacerbations (1 year) and future exacerbations (3 years)
| Future exacerbations (1 year)# | |||
|---|---|---|---|
| No (n=111)¶ | Yes (n=39)¶ | p-value+ | |
| Median (Q1, Q3) or n (%) | median (Q1, Q3) or n (%) | ||
| IOS Rrs5 | |||
| Z-score, continuous | 1.15 (0.65, 1.52) | 1.34 (1.07, 2.02) | 0.013 |
| Abnormal z-score§ | 22 (22) | 11 (37) | 0.093 |
| FOT Rrs5 | |||
| Z-score, continuous | 0.73 (−0.51, 1.68) | 1.32 (0.32, 2.28) | 0.004 |
| Abnormal z-score§ | 28 (25) | 18 (46) | 0.015 |
| IOS Xrs5 | |||
| Z-score, continuous | −0.92 (−1.76, −0.49) | −1.75 (−2.39, −0.91) | 0.011 |
| Abnormal z-scoreƒ | 29 (28) | 17 (57) | 0.004 |
| FOT Xrs5 | |||
| Z-score, continuous | −0.55 (−3.50, 0.73) | −2.56 (−7.49, −0.15) | 0.003 |
| Abnormal z-scoreƒ | 40 (36) | 22 (56) | 0.026 |
| FOT ΔXrs5 | |||
| Abnormal ΔXrs5## | 15 (14) | 13 (33) | <0.001 |
| Future exacerbations (3 year)# | |||
|---|---|---|---|
| No (n=77)¶¶ | Yes (n=73)¶¶ | p-value+ | |
| Median (Q1, Q3) or n (%) | median (Q1, Q3) or n (%) | ||
| IOS Rrs5 | |||
| Z-score, continuous | 1.10 (0.64, 1.40) | 1.315 (1.03, 1.68) | 0.004 |
| Abnormal z-score§ | 15 (21) | 18 (30) | 0.268 |
| FOT Rrs5 | |||
| Z-score, continuous | 0.56 (−0.56, 1.50) | 1.15 (0.25, 2.25) | 0.008 |
| Abnormal z-score§ | 17 (22) | 29 (40) | 0.019 |
| IOS Xrs5 | |||
| Z-score, continuous | −0.85 (−1.76, −0.49) | −1.35 (−2.19, −0.74) | 0.049 |
| Abnormal z-score ƒ | 20 (28) | 26 (43) | 0.082 |
| FOT Xrs5 | |||
| Z-score, continuous | −0.17 (−3.01, 0.73) | −1.59 (−5.50, 0.40) | 0.015 |
| Abnormal z-score ƒ | 26 (34) | 36 (49) | 0.053 |
| FOT ΔXrs5 | |||
| Abnormal ΔXrs5## | 11 (14) | 17 (23) | 0.157 |
Q1: first quartile (25th percentile); Q3: third quartile (75th percentile). #: future exacerbations (1 and 3 years) were defined as having ≥1 exacerbation between baseline and 1 and 3 years after the inclusion visit, respectively. ¶: numbers are given for participants with FOT measurements; the corresponding numbers for participants with IOS measurements are 102 for “no” and 30 for “yes”. +: Mann-Whitney U test or Chi2 test. §: abnormal IOS Rrs5 z-scores [19] and abnormal FOT Rrs5 z-scores [9] were defined as values >1.645 sd. ƒ: abnormal IOS Xrs5 z-scores [19] and abnormal FOT Xrs5 z-scores [9] were defined as values <−1.645 sd. ##: abnormal FOT ΔXrs5 was defined as a mean difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s−1. ¶¶: numbers are given for participants with FOT measurements; the corresponding numbers for participants with IOS measurements are 71 for “no” and 61 for “yes”.
FIGURE 1.
The prevalence of severe airway obstruction, moderate to severe COPD health status and dyspnoea, future exacerbations (1 and 3 years) among participants with both abnormal resistance of the respiratory system at 5 Hz (Rrs5) and reactance of the respiratory system at 5 Hz (Xrs5) by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150) post salbutamol inhalation. The illustration was created with GraphPad Prism 10. Abnormal Rrs5 and Xrs5 by IOS were defined as z-scores >1.645 and <−1.645 sd, respectively [19]. Abnormal Rrs5 and Xrs5 by FOT were defined as z-scores >1.645 and <−1.645 sd, respectively [9]. Severe airway obstruction was defined as forced expiratory volume in 1 s <50% pred. Moderate/severe COPD health status corresponded to a COPD Assessment Test score ≥10. Moderate/severe dyspnoea corresponded to a modified British Medical Research Council dyspnoea score ≥2. Future exacerbations (1 and 3 years) were defined as having ≥1 exacerbation between baseline and 1 and 3 years after the inclusion visit, respectively.
There was no difference in the prevalence of abnormal Rrs5 and Xrs5 in relation to the mean number of future exacerbations (3 years). However, abnormal Rrs5 by FOT differed, showing an increasing frequency with accumulating exacerbations: 17/77 (22%), 16/44 (36%) and 13/29 (45%), respectively (p=0.048). No differences in the prevalence of abnormal ΔXrs5 by the mean number of future exacerbations (3 years) were found (supplementary table 1).
Associations between IOS indices and disease burden
Abnormal Rrs5 and Xrs5 were associated with severe airway obstruction with an adjusted odds ratio ranging from 4.80 (95% CI 1.93–12.0) to 18.0 (95% CI 7.13–45.3). While an association between abnormal Rrs5 by IOS and moderate to severe COPD health status were seen (OR 3.45, 95% CI 1.16–10.3), no significant associations were found between abnormal Rrs5 and Xrs5 and dyspnoea. Associations between Rrs5 and Xrs5 and future exacerbations (1 year) were observed, as follows: OR 3.09 (95% CI 1.26–7.57) for Rrs5 by FOT and OR 2.81 (95% CI 1.13–6.99) for Xrs5 by IOS. Only abnormal Rrs5 by FOT was associated with future exacerbations (3 years), with an OR 2.77 (95% CI 1.27–6.05) (table 5 and supplementary table 2). In participants with both abnormal Rrs5 and Xrs5 by IOS (n=26), odds ratios for severe airway obstruction and future exacerbations (1 year) increased by 8.04 (95% CI 2.87–22.5) and 3.17 (95% CI 1.09–9.17), respectively. Similarly, in the presence of both abnormal Rrs5 and Xrs5 by FOT (n=38), the odds ratios for severe airway obstruction and future exacerbations (1 and 3 years) increased to 10.4 (95% CI 4.20–26.0), 2.64 (95% CI 1.07–6.54) and 2.52 (95% CI 1.12–5.68), respectively. No correlations were seen to moderate to severe COPD health status or dyspnoea (figure 2 and supplementary table 3). Abnormal ΔXrs5 was associated with severe airway obstruction, moderate to severe COPD health status and dyspnoea, with odds ratios of 12.1 (95% CI 4.16–35.0), 3.86 (95% CI 1.05–14.2) and 3.98 (95% CI 1.38–11.5), respectively. The associations between abnormal ΔXrs5 and future exacerbations (1 and 3 years) remained nonsignificant (table 5 and supplementary table 2).
TABLE 5.
Adjusted logistic regression of z-scores and abnormal z-scores for resistance of the respiratory system at 5 Hz (Rrs5), reactance of the respiratory system at 5 Hz (Xrs5) and mean difference in Xrs5 (ΔXrs5) by impulse oscillometry (IOS) (n=132) and/or the forced oscillation technique (FOT) (n=150) indices post salbutamol inhalation and severity of airway obstruction, COPD health status, dyspnoea and future exacerbations (1 and 3 years)
| Severe airway obstruction# | Moderate/severe COPD health status¶ | Moderate/severe dyspnoea+ | Future exacerbations (1 year)§ | Future exacerbations (3 years)§ | |
|---|---|---|---|---|---|
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| IOS Rrs5 | |||||
| Z-score, continuous | 3.91 (1.98–7.74) | 1.32 (0.81–2.14) | 1.54 (0.94–2.50) | 2.39 (1.32–4.34) | 2.29 (1.34–3.90) |
| Abnormal z-scoreƒ | 4.80 (1.93–12.0) | 3.45 (1.16–10.3) | 1.21 (0.49–2.97) | 2.47 (0.91–6.72) | 1.89 (0.81–4.43) |
| FOT Rrs5 | |||||
| Z-score, continuous | 4.09 (2.46–6.78) | 1.05 (0.80–1.36) | 1.18 (0.91–1.54) | 1.42 (1.03–1.95) | 1.35 (1.04–1.74) |
| Abnormal z-scoreƒ | 16.8 (6.33–44.8) | 1.32 (0.58–2.99) | 0.92 (0.42–2.03) | 3.09 (1.26–7.57) | 2.77 (1.27–6.05) |
| IOS Xrs5 | |||||
| Z-score, continuous | 0.35 (0.22–0.55) | 0.70 (0.47–1.03) | 0.73 (0.52–1.02) | 0.73 (0.51–1.05) | 0.82 (0.60–1.11) |
| Abnormal z-score## | 12.2 (5.06– 29.5) | 2.04 (0.86–4.87) | 1.54 (0.70–3.41) | 2.81 (1.13–6.99) | 1.77 (0.83–3.79) |
| FOT Xrs5 | |||||
| Z-score, continuous | 0.67 (0.58–0.78) | 0.93 (0.84–1.03) | 0.90 (0.81–0.98) | 0.92 (0.84–1.01) | 0.92 (0.84–1.00) |
| Abnormal z-score## | 18.0 (7.13–45.3) | 2.04 (0.95–4.38) | 1.72 (0.83–3.57) | 1.84 (0.82–4.13) | 1.76 (0.88–3.52) |
| FOT ΔXrs5 | |||||
| Abnormal ΔXrs5¶¶ | 12.1 (4.16–35.0) | 3.86 (1.05– 14.2) | 3.98 (1.38–11.5) | 2.36 (0.88–6.36) | 1.64 (0.65–4.12) |
Logistic regression models adjusted for sex, age, current smoking and exacerbations 1 year before inclusion. Significant associations do not include 1 (shown in bold). #: defined as a forced expiratory volume in 1 s <50% pred. ¶: corresponding to a COPD Assessment Test score ≥10. +: corresponding to a modified Medical Research Council dyspnoea score ≥2. §: future exacerbations (1 and 3 years) were defined as having ≥1 exacerbation between baseline and 1 and 3 years after the inclusion visit, respectively. ƒ: abnormal IOS Rrs5 z-scores [19] and abnormal FOT Rrs5 z-scores [9] were defined as values >1.645 sd. ##: abnormal IOS Xrs5 z-scores [19] and abnormal FOT Xrs5 z-scores [9] were defined as values <−1.645 sd. ¶¶: abnormal FOT ΔXrs5 was defined as a mean within-breath difference in Xrs5 between inspiration and expiration >2.80 cmH2O·L−1·s−1.
FIGURE 2.
Adjusted odds ratios (95% confidence interval) for severe airway obstruction, moderate to severe COPD health status and dyspnoea, future exacerbations (1 and 3 years) according to the presence of having both abnormal resistance of the respiratory system at 5 Hz (Rrs5) and reactance of the respiratory system at 5 Hz (Xrs5) by impulse oscillometry (IOS) (n=132) and the forced oscillation technique (FOT) (n=150). Significant associations do not include 1 (marked with #). Abnormal Rrs5 and Xrs5 by IOS were defined as z-scores >1.645 and <−1.645 sd, respectively [19]. Abnormal Rrs5 and Xrs5 by FOT were defined as z-scores >1.645 and <−1.645 sd, respectively [9]. Severe airway obstruction was defined as a forced expiratory volume in 1 s <50% pred. Moderate/severe COPD health status corresponded to a COPD Assessment Test score ≥10. Moderate/severe dyspnoea corresponded to a modified British Medical Research Council dyspnoea score ≥2. Future exacerbations (1 and 3 years) were defined as having ≥1 exacerbation between baseline and 1 and 3 years after the inclusion visit, respectively. The illustration was created with GraphPad Prism 10. #: Logistic regression models adjusted for sex, age, current smoking and exacerbations 1 year before inclusion.
No significant interaction effects were observed for severe airway obstruction or asthma on the relationship between IOS or FOT indices and moderate to severe COPD health status, dyspnoea or future exacerbations (1 or 3 years) (all p-values >0.05).
Discussion
In this observational study of 150 Swedish adults with COPD, Rrs5, Xrs5 and ΔXrs5 by IOS and FOT largely differed across participants with and without severe airway obstruction, moderate to severe COPD health status, dyspnoea and future exacerbations (1 and 3 years). Correspondingly, the Rrs5, Xrs5 and/or ΔXrs5 overall correlated to disease burden, with the highest risk observed for severe airway obstruction, followed by moderate to severe dyspnoea, COPD health status and future exacerbations (1 and 3 years).
Abnormal Rrs5, Xrs5 and ΔXrs5 by IOS and FOT were linked to severe airway obstruction, in line with several studies [11, 22–27]. The association between abnormal ΔXrs5 and severity of airway obstruction is novel. In both the multicentre ECLIPSE trial (n=2164) [11] and the Chinese ECOPD study (n=768) [25], higher Rrs5 and lower Xrs5 by IOS were found in COPD patients with severe airway obstruction. In three smaller COPD reports from China (n=215) [24], India (n=196) [22] and Italy (n=202) [27], the same trends for Rrs5 and Xrs5 by IOS and FOT were seen, further supporting our findings. Correspondingly, in a Turkish study (n=48), Duman et al. [26] reported associations between Rrs5 and Xrs5 by IOS and airway obstruction in COPD. In the Indian study by Rath et al. [22], the prevalence of abnormal ΔXrs5 by FOT increased in tandem with airway obstruction. Furthermore, in a British study of 70 COPD participants, abnormal ΔXrs5 by IOS was more common with higher stages of airway obstruction [23].
Abnormal Rrs5, Xrs5 and ΔXrs5 by IOS and/or FOT were more frequent in moderate to severe COPD health status. Similarly, abnormal Xrs5 and ΔXrs5 by FOT were more common in the presence of moderate to severe dyspnoea. Whereas abnormal ΔXrs5 correlated with both COPD health status and dyspnoea, abnormal Rrs5 by IOS was related only to COPD health status. Apart from the novel finding of a link between abnormal ΔXrs5 and dyspnoea, our observations correspond with previous reports [25, 28–33]. In the ECOPD trial [25], the prevalence of abnormal Rrs5 and Xrs5 by IOS was higher in participants with more severe COPD health status and dyspnoea. In a Japanese study by Haruna et al. [30] (n=65) and a Scandinavian report (n=112) by Obling et al. [31], links between Rrs5 and Xrs5 by IOS and COPD health status were found, supporting our findings. In the studies by Duman et al. [26] and Haruna et al. [30], Rrs5 or Xrs5 by IOS related to the dyspnoea severity. However, the study populations were smaller, included mostly males and the authors only reported crude associations [26, 30]. Regarding expiratory flow limitation, in a British study (n=145), abnormal ΔXrs5 by IOS was linked to more severe COPD health status [28]. Similarly, in a Swedish study (n=96), abnormal ΔXrs5 by FOT was associated with COPD health status severity [32]. Using two different cutoffs (>2.80 and >1.00 cmH2O·L−1·s−1), abnormal ΔXrs5 was observed in patients with more dyspnoea in two Norwegian ECLIPSE sub studies (n=425) [29, 33], suggesting both thresholds for expiratory flow limitation may be pathological in COPD.
Although we may be first to report that abnormal Rrs5 and Xrs5 by IOS and/or FOT were related to future exacerbations (1 and 3 years), our findings are in line with previous reports assessing the relationships between FOT and previous, concurrent and future exacerbations [12, 25, 34]. The observation of abnormal ΔXrs5 being more prevalent in future exacerbators (1 year) is a novel finding. In the Japanese study by Zhang et al. [34] (n=134), Rrs5 and Xrs5 by FOT appeared to increase and decrease with the number of COPD exacerbations up to 5 years, respectively. In the same study, Rrs5 and Xrs5 similarly correlated to future exacerbations [34], in line with the findings in the ECOPD trial assessing the relationship to exacerbations in the previous year [25], However, in the paper by Zhang et al. [34], associations between Rrs5 and Xrs5 remained nonsignificant in multivariate survival analyses. Moreover, only males were included and a different FOT technique (MostGraph-01, Chest MI Corp., Tokyo, Japan) was used [34]. Using that same equipment, another Japanese study reported a more negative Xrs5 in concurrent exacerbators than nonexacerbators with COPD, but found no differences in ΔXrs5 [12]. While the latter observation is in contrast to our results, the study population was slightly smaller (n=119) and primarily consisted of males (89%) [12]. Abnormal ΔXrs5 by IOS was linked to a lower risk of future exacerbations in our study than in the ECLIPSE trial, a significantly larger COPD study (n=425), in which survival analysis was used to assess potential associations [33].
A strength of the present study is the inclusion of both male and female participants from primary (72%) and secondary care settings, increasing the likelihood of capturing a population representative of Swedish COPD patients, thereby increasing the generalisability. The thorough investigation, in which COPD was confirmed by spirometry, ensured a well-characterised study population and is a major strength. Other strengths of this study are the use of both IOS and FOT measurements, the application of available reference values for Rrs5 and Xrs5 [9, 19], and the well-established cutoff for ΔXrs5 [13, 19]. Although the fit of existing reference values remains debatable, continuous and dichotomised z-scores for the oscillometry indices were presented in line with the existing guidelines [7]. In our material, only 50% of the patients had abnormal oscillometry, but is in line with the prevalence in the ECOPD trial (60%) [25]. Similarly, in a large population-based study from Sweden, only 30% of the participants with obstruction had abnormal oscillometry [35]. To simplify the presentation of our results, we focused on abnormal oscillometry indices. However, the continuous z-scores revealed several important findings, supporting our results. Unlike airway obstruction and future exacerbations, based on objective spirometry measurements and medical records, the COPD health status and dyspnoea relied on self-reported CAT and mMRC scores. In the patient questionnaire, no distinction between current or ever diagnosed asthma was made and is a major limitation. While current technical standards recommend using the mean of three consecutive oscillatory measurements [7], the mean of two was used. However, in a population-based sample of 700 Swedish adults, the variation between a single IOS measurement and the mean of three appeared minimal, suggesting one may suffice [36]. Correspondingly, in larger epidemiological studies such as the Austrian LEAD study (n=7560), a single FOT measurement was obtained [21].
In summary, Rrs5, Xrs5 and/or ΔXrs5 by IOS and/or FOT overall related to the severity of airway obstruction, COPD health status, dyspnoea and future exacerbations (1 and 3 years). Given that oscillometry is an effort-independent lung function test and is becoming increasingly accessible in clinical settings, one may speculate that IOS and FOT may prove useful as complements to spirometry at annual follow-ups, particularly in patients unable to perform forced expiratory manoeuvres. However, larger longitudinal studies are needed to determine the clinical usefulness of oscillometry in COPD disease monitoring and management.
Acknowledgements
We sincerely thank all participants in the TIE study and the study personnel who contributed to enrolling and managing the study.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: The TIE study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the Regional Ethics Review Board in Uppsala, Sweden (dnr 2013/358). Informed written consent was collected from all participants at enrolment.
Author contributions: M. Färdig and K. Lingman contributed equally to conception and design of the study, analysis and interpretation of data, manuscript writing and editing. K. Lisspers, B. Ställberg, C. Janson, M. Högman and A. Malinovschi contributed to conception and design of the study, data acquisition, interpretation of data, and critically revised the manuscript. A. Malinovschi supervised the manuscript writing. All listed authors approved the final version of the manuscript before submission and agreed to be accountable for all aspects of the work.
Conflict of interest: The authors have nothing to disclose.
Support statement: The TIE study has received funding from the following sources: Regional Research Council Mid Sweden, the Centre for Research and Development, Uppsala University/Region Gävleborg, the Center for Clinical Research Dalarna–Uppsala University, the Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Heart and Lung Association, and the Bror Hjerpstedt Foundation. Additional funding was provided by the economic support for clinical research arranged by the Disciplinary Domain of Medicine and Pharmacy, Uppsala University, Sweden. The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report or the decision to submit. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
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