Combining low-frequency oscillometry and spirometry measurements in relation to asthma control and exacerbations in moderate-to-severe asthma
2022; Elsevier BV; Volume: 10; Issue: 7 Linguagem: Inglês
10.1016/j.jaip.2022.03.023
ISSN2213-2201
Autores Tópico(s)Phonocardiography and Auscultation Techniques
ResumoClinical ImplicationsPatients with combined impairment of reactance at 5 Hz (X5) and forced expiratory volume in 1 second have significantly worse asthma control and more frequent severe exacerbations.Respiratory oscillometry is an effort-independent pulmonary function test that can assess respiratory impedance over a range of frequencies, comprising resistance (R) and reactance (X) moieties. Governed by Poiseuille's law, airway resistance is largely determined by airway caliber and length, whereas reactance comprises elastance and inertance components and can be used as a measurement for lung stiffness at various frequencies. Low-frequency sound waves penetrate further down the airways and hence reflect changes in the whole lung. Therefore, total airway resistance can be assessed by measuring at 5 Hz (R5), whereas airway compliance can be assessed as reactance at 5 Hz (X5).1King G.G. Bates J. Berger K.I. Calverley P. de Melo P.L. Dellacà R.L. et al.Technical standards for respiratory oscillometry.Eur Respir J. 2020; 55: 1900753Crossref PubMed Scopus (163) Google Scholar Recently it has been shown that adults with a positive bronchodilator response assessed by R5 or X5 have a higher prevalence of asthma and wheezing.2Johansson H. Wollmer P. Sundström J. Janson C. Malinovschi A. Bronchodilator response in FOT parameters in middle-aged adults from SCAPIS: normal values and relationship to asthma and wheezing.Eur Respir J. 2021; 58: 2100229Crossref PubMed Scopus (4) Google Scholar Furthermore, X5 has greater sensitivity in identifying poor asthma control than spirometry.3Cottee A.M. Seccombe L.M. Thamrin C. King G.G. Peters M.J. Farah C.S. Bronchodilator response assessed by the forced oscillation technique identifies poor asthma control with greater sensitivity than spirometry.Chest. 2020; 157: 1435-1441Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Nonetheless, spirometry measurement of forced expiratory volume in 1 second (FEV1) still remains the main investigation of choice in current global asthma guidelines.4Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention Main Report 2021.https://ginasthma.org/Date accessed: December 11, 2021Google ScholarCombining oscillometry and spirometry measurements together may be useful in identifying poor asthma control defined by increased use of oral corticosteroids (OCS) and short-acting β-agonists in relation to small airways function as resistance heterogeneity between 5 and 20 Hz (R5-R20) and forced expiratory flow rate between 25% and 75% of forced vital capacity (FEF25-75%).5Manoharan A. Anderson W.J. Lipworth J. Ibrahim I. Lipworth B.J. Small airway dysfunction is associated with poorer asthma control.Eur Respir J. 2014; 44: 1353-1355Crossref PubMed Scopus (44) Google Scholar Although R5-R20 correlates with FEF25-75, the current significance of FEF25-75 is still somewhat debated.In the study, we evaluate asthma control as the Asthma Control Questionnaire (ACQ), OCS-requiring severe exacerbations, and type 2 (T2) biomarkers (peripheral blood eosinophils, fractional exhaled nitric oxide, and total and specific IgE) in adult moderate-to-severe asthma patients with impaired oscillometry with or without impaired spirometry.Data from 94 respiratory physician-diagnosed moderate-to-severe asthma patients were retrospectively collected from outpatients attending our unit during normal clinical evaluation. Patients were divided into 2 groups based on the interplay between oscillometry and spirometry measurements: (a) impaired X5 (or R5) with impaired FEV1 and (b) impaired X5 (or R5) with preserved FEV1. Values of −0.20 kPa/L/s for X5, 0.50 kPa/L/s for R5, and 80% for FEV1 were chosen to define impairment.Fractional exhaled nitric oxide (FeNO) was measured using NIOX VERO (Circassia, Oxford, UK) according to the manufacturer's instructions and American Thoracic Society (ATS) guidelines. Spirometry (Micro Medical, Chatham, UK) was performed according to European Respiratory Society (ERS)/ATS guidelines. Oscillometry was measured using either IOS Masterscreen (Carefusion, Hoechberg, Germany) or TremoFlo (Thorasys, Montreal, QC, Canada). Measurements were performed in triplicate to assess oscillometry according to the ERS technical standards with oscillometry always performed before spirometry. Blood testing was performed for peripheral blood eosinophils, total IgE (kU/L), and number of positive specific IgE antibodies (fluorescence enzyme linked immunoassay [Phadia Immunocap 250]) to defined common allergens including house dust mite, grass, cat, dog, and silver birch. In patients taking biologics, data on T2 biomarkers (peripheral blood eosinophils, FeNO, and total and specific IgE) preceded treatment initiation to avoid potential confounding. Asthma control was determined using the 6-point ACQ. The number of OCS-requiring asthma exacerbations in the preceding year was noted, determined by an oral prednisolone dose of 40 mg daily for at least 5 consecutive days.Statistical analysis was performed using SPSS version 27 (Portsmouth, UK). Data were initially assessed for outliers and normality before analysis. Independent Student's t tests were performed to evaluate any significant differences in ACQ, OCS-requiring exacerbations, T2 biomarkers, and pulmonary function between the 2 groups using a 2-tailed alpha error set at 0.05. Data for R5-R20 were logarithmically transformed to normalize its distribution before analysis. Values provided in this paper are all arithmetic means (95% confidence interval [CI]) except for R5-R20 where geometric mean (95% CI) was used. Caldicott approval was obtained for National Health Service patients, whereas for clinical trial patients, ethical approval was obtained via the East of Scotland research ethics service before data collection.The mean overall demographic data were as follows: gender (F/M) 72/22; age 52; body mass index 32.7 kg/m2; inhaled corticosteroid beclomethasone dipropionate equivalent dose 1694 μg; percentage of patients taking long-acting β-agonist 78%; long-acting muscarinic-antagonist 53%; leukotriene receptor antagonist 59%; theophylline 22%; oral antihistamines 54%; anti-IL5(rα) 18%; anti-IL4rα 4%; FEV1 76%; FEF25-75 41%; and R5 209%.Table I and Table E1 (available in this article's Online Repository at www.jaci-inpractice.org) present significant differences in ACQ, OCS-requiring exacerbations, T2 biomarkers, and pulmonary function in patients with impaired oscillometry (R5 or X5) with or without impaired spirometry (FEV1). Patients with combined impairment of X5 and FEV1 had significantly worse ACQ, OCS-requiring exacerbations, R5-R20, and AX than those with impaired X5 but preserved FEV1 (Figure 1). A similar pattern was seen for patients with combined impairment of R5 and FEV1, aside from OCS-requiring exacerbations that were borderline significant (P = .05) (Figure 1). FeNO was significantly worse in patients with combined impairment of R5 and FEV1, but no differences were observed for other T2 biomarkers.Table ISignificant comparisons in Asthma Control Questionnaire (ACQ), oral corticosteroid (OCS) exacerbations, and type 2 biomarkers in patients with impaired oscillometry with or without impaired spirometryClinical outcomesR5 ≥ 0.5 kPa/L/sX5 ≤ −0.2 kPa/L/sFEV1 ≥ 80%FEV1 < 80%FEV1 ≥ 80%FEV1 < 80%ACQ2.2 (1.8-2.7) (n = 42)2.9 (2.5-3.3)∗P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. (n = 44)2.2 (1.8-2.7) (n = 25)2.9 (2.5-3.3)∗P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. (n = 35)OCS exacerbations2.3 (1.5-3.1) (n = 31)3.3 (2.6-4.0)∗P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. (n = 39)1.8 (0.7-2.9) (n = 18)3.2 (2.5-4.0)∗P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. (n = 30)FeNO (ppb)24 (17-32) (n = 36)36 (27-44)∗P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. (n = 38)27 (17-37) (n = 25)35 (26-43) (n = 32)PBE (cells/μL)329 (258-400) (n = 42)324 (247-401) (n = 44)308 (241-374) (n = 25)289 (203-376) (n = 34)No. of positive specific IgE1.4 (0.8-2.0) (n = 33)1.7 (1.1-2.3) (n = 33)1.1 (0.5-1.7) (n = 20)1.3 (0.7-1.9) (n = 27)Total IgE (kU/L)338 (183-494) (n = 34)296 (206-387) (n = 40)248 (139-357) (n = 20)262 (171-354) (n = 29)Values presented as arithmetic means (95% CI) except for R5-R20 where geometric means (95% CI) were used. Specific IgE are shown as the mean number of positive responses ≥0.35 kUA/L.CI, Confidence interval; FeNO; fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.∗ P = .05, P < .05, denotes significant comparisons between groups for either FEV1 ≥ 80% or FEV1 < 80%. Open table in a new tab Our results show that patients with combined impairment of X5 and FEV1 had a 78% higher exacerbation risk and a mean 0.7-unit higher ACQ score than those with impaired X5 but preserved FEV1 (Table I), in keeping with clinically relevant differences in disease control. On the contrary, T2 biomarkers including FeNO, peripheral blood eosinophils, and specific and total IgE were not significantly different when comparing patients with impaired X5 with or without impaired FEV1. The only notable exception was FeNO in the impaired R5 with or without FEV1 impairment analysis, but this did not exceed the biological variability value of 15 for severe asthma.6Chan R. Misirovs R. Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma.Eur Respir J. 2021; 59: 2101679Crossref PubMed Scopus (4) Google ScholarMoreover, patients with combined impairment of X5 and FEV1 had significantly worse indicators of small airways disease expressed as either R5-R20 or AX than those with impaired X5 but preserved FEV1. The observed differences of 0.12 kPa/L/s for R5-R20 and 2.63 kPa/L for AX greatly exceeded previously reported biological variability values of 0.04 kPa/L/s and 0.39 kPa/L, respectively, inferring that these differences are likely to be clinically relevant.6Chan R. Misirovs R. Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma.Eur Respir J. 2021; 59: 2101679Crossref PubMed Scopus (4) Google Scholar In turn, small airways dysfunction is associated with poor asthma control in asthma.7Kuo C.R. Jabbal S. Lipworth B. Is small airways dysfunction related to asthma control and type 2 inflammation?.Ann Allergy Asthma Immunol. 2018; 121: 631-632Abstract Full Text Full Text PDF PubMed Scopus (16) Google ScholarThere are limitations associated with these data including its retrospective nature. Furthermore, we appreciate that in real-life clinical practice, most clinicians would use spirometry rather than oscillometry as a starting point. We chose pragmatic cutoff values for oscillometry and spirometry that we routinely employ in our service clinic to denote clinically abnormal values. Our findings highlight the potential advantage of combining both spirometry and oscillometry measurements in fully characterizing airflow limitation in moderate-to-severe asthma. Clinical ImplicationsPatients with combined impairment of reactance at 5 Hz (X5) and forced expiratory volume in 1 second have significantly worse asthma control and more frequent severe exacerbations. Patients with combined impairment of reactance at 5 Hz (X5) and forced expiratory volume in 1 second have significantly worse asthma control and more frequent severe exacerbations. Patients with combined impairment of reactance at 5 Hz (X5) and forced expiratory volume in 1 second have significantly worse asthma control and more frequent severe exacerbations. Respiratory oscillometry is an effort-independent pulmonary function test that can assess respiratory impedance over a range of frequencies, comprising resistance (R) and reactance (X) moieties. Governed by Poiseuille's law, airway resistance is largely determined by airway caliber and length, whereas reactance comprises elastance and inertance components and can be used as a measurement for lung stiffness at various frequencies. Low-frequency sound waves penetrate further down the airways and hence reflect changes in the whole lung. Therefore, total airway resistance can be assessed by measuring at 5 Hz (R5), whereas airway compliance can be assessed as reactance at 5 Hz (X5).1King G.G. Bates J. Berger K.I. Calverley P. de Melo P.L. Dellacà R.L. et al.Technical standards for respiratory oscillometry.Eur Respir J. 2020; 55: 1900753Crossref PubMed Scopus (163) Google Scholar Recently it has been shown that adults with a positive bronchodilator response assessed by R5 or X5 have a higher prevalence of asthma and wheezing.2Johansson H. Wollmer P. Sundström J. Janson C. Malinovschi A. Bronchodilator response in FOT parameters in middle-aged adults from SCAPIS: normal values and relationship to asthma and wheezing.Eur Respir J. 2021; 58: 2100229Crossref PubMed Scopus (4) Google Scholar Furthermore, X5 has greater sensitivity in identifying poor asthma control than spirometry.3Cottee A.M. Seccombe L.M. Thamrin C. King G.G. Peters M.J. Farah C.S. Bronchodilator response assessed by the forced oscillation technique identifies poor asthma control with greater sensitivity than spirometry.Chest. 2020; 157: 1435-1441Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Nonetheless, spirometry measurement of forced expiratory volume in 1 second (FEV1) still remains the main investigation of choice in current global asthma guidelines.4Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention Main Report 2021.https://ginasthma.org/Date accessed: December 11, 2021Google Scholar Combining oscillometry and spirometry measurements together may be useful in identifying poor asthma control defined by increased use of oral corticosteroids (OCS) and short-acting β-agonists in relation to small airways function as resistance heterogeneity between 5 and 20 Hz (R5-R20) and forced expiratory flow rate between 25% and 75% of forced vital capacity (FEF25-75%).5Manoharan A. Anderson W.J. Lipworth J. Ibrahim I. Lipworth B.J. Small airway dysfunction is associated with poorer asthma control.Eur Respir J. 2014; 44: 1353-1355Crossref PubMed Scopus (44) Google Scholar Although R5-R20 correlates with FEF25-75, the current significance of FEF25-75 is still somewhat debated. In the study, we evaluate asthma control as the Asthma Control Questionnaire (ACQ), OCS-requiring severe exacerbations, and type 2 (T2) biomarkers (peripheral blood eosinophils, fractional exhaled nitric oxide, and total and specific IgE) in adult moderate-to-severe asthma patients with impaired oscillometry with or without impaired spirometry. Data from 94 respiratory physician-diagnosed moderate-to-severe asthma patients were retrospectively collected from outpatients attending our unit during normal clinical evaluation. Patients were divided into 2 groups based on the interplay between oscillometry and spirometry measurements: (a) impaired X5 (or R5) with impaired FEV1 and (b) impaired X5 (or R5) with preserved FEV1. Values of −0.20 kPa/L/s for X5, 0.50 kPa/L/s for R5, and 80% for FEV1 were chosen to define impairment. Fractional exhaled nitric oxide (FeNO) was measured using NIOX VERO (Circassia, Oxford, UK) according to the manufacturer's instructions and American Thoracic Society (ATS) guidelines. Spirometry (Micro Medical, Chatham, UK) was performed according to European Respiratory Society (ERS)/ATS guidelines. Oscillometry was measured using either IOS Masterscreen (Carefusion, Hoechberg, Germany) or TremoFlo (Thorasys, Montreal, QC, Canada). Measurements were performed in triplicate to assess oscillometry according to the ERS technical standards with oscillometry always performed before spirometry. Blood testing was performed for peripheral blood eosinophils, total IgE (kU/L), and number of positive specific IgE antibodies (fluorescence enzyme linked immunoassay [Phadia Immunocap 250]) to defined common allergens including house dust mite, grass, cat, dog, and silver birch. In patients taking biologics, data on T2 biomarkers (peripheral blood eosinophils, FeNO, and total and specific IgE) preceded treatment initiation to avoid potential confounding. Asthma control was determined using the 6-point ACQ. The number of OCS-requiring asthma exacerbations in the preceding year was noted, determined by an oral prednisolone dose of 40 mg daily for at least 5 consecutive days. Statistical analysis was performed using SPSS version 27 (Portsmouth, UK). Data were initially assessed for outliers and normality before analysis. Independent Student's t tests were performed to evaluate any significant differences in ACQ, OCS-requiring exacerbations, T2 biomarkers, and pulmonary function between the 2 groups using a 2-tailed alpha error set at 0.05. Data for R5-R20 were logarithmically transformed to normalize its distribution before analysis. Values provided in this paper are all arithmetic means (95% confidence interval [CI]) except for R5-R20 where geometric mean (95% CI) was used. Caldicott approval was obtained for National Health Service patients, whereas for clinical trial patients, ethical approval was obtained via the East of Scotland research ethics service before data collection. The mean overall demographic data were as follows: gender (F/M) 72/22; age 52; body mass index 32.7 kg/m2; inhaled corticosteroid beclomethasone dipropionate equivalent dose 1694 μg; percentage of patients taking long-acting β-agonist 78%; long-acting muscarinic-antagonist 53%; leukotriene receptor antagonist 59%; theophylline 22%; oral antihistamines 54%; anti-IL5(rα) 18%; anti-IL4rα 4%; FEV1 76%; FEF25-75 41%; and R5 209%. Table I and Table E1 (available in this article's Online Repository at www.jaci-inpractice.org) present significant differences in ACQ, OCS-requiring exacerbations, T2 biomarkers, and pulmonary function in patients with impaired oscillometry (R5 or X5) with or without impaired spirometry (FEV1). Patients with combined impairment of X5 and FEV1 had significantly worse ACQ, OCS-requiring exacerbations, R5-R20, and AX than those with impaired X5 but preserved FEV1 (Figure 1). A similar pattern was seen for patients with combined impairment of R5 and FEV1, aside from OCS-requiring exacerbations that were borderline significant (P = .05) (Figure 1). FeNO was significantly worse in patients with combined impairment of R5 and FEV1, but no differences were observed for other T2 biomarkers. Values presented as arithmetic means (95% CI) except for R5-R20 where geometric means (95% CI) were used. Specific IgE are shown as the mean number of positive responses ≥0.35 kUA/L. CI, Confidence interval; FeNO; fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second. Our results show that patients with combined impairment of X5 and FEV1 had a 78% higher exacerbation risk and a mean 0.7-unit higher ACQ score than those with impaired X5 but preserved FEV1 (Table I), in keeping with clinically relevant differences in disease control. On the contrary, T2 biomarkers including FeNO, peripheral blood eosinophils, and specific and total IgE were not significantly different when comparing patients with impaired X5 with or without impaired FEV1. The only notable exception was FeNO in the impaired R5 with or without FEV1 impairment analysis, but this did not exceed the biological variability value of 15 for severe asthma.6Chan R. Misirovs R. Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma.Eur Respir J. 2021; 59: 2101679Crossref PubMed Scopus (4) Google Scholar Moreover, patients with combined impairment of X5 and FEV1 had significantly worse indicators of small airways disease expressed as either R5-R20 or AX than those with impaired X5 but preserved FEV1. The observed differences of 0.12 kPa/L/s for R5-R20 and 2.63 kPa/L for AX greatly exceeded previously reported biological variability values of 0.04 kPa/L/s and 0.39 kPa/L, respectively, inferring that these differences are likely to be clinically relevant.6Chan R. Misirovs R. Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma.Eur Respir J. 2021; 59: 2101679Crossref PubMed Scopus (4) Google Scholar In turn, small airways dysfunction is associated with poor asthma control in asthma.7Kuo C.R. Jabbal S. Lipworth B. Is small airways dysfunction related to asthma control and type 2 inflammation?.Ann Allergy Asthma Immunol. 2018; 121: 631-632Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar There are limitations associated with these data including its retrospective nature. Furthermore, we appreciate that in real-life clinical practice, most clinicians would use spirometry rather than oscillometry as a starting point. We chose pragmatic cutoff values for oscillometry and spirometry that we routinely employ in our service clinic to denote clinically abnormal values. Our findings highlight the potential advantage of combining both spirometry and oscillometry measurements in fully characterizing airflow limitation in moderate-to-severe asthma. Online RepositoryTable E1Significant comparisons in pulmonary function in patients with impaired oscillometry with or without impaired spirometryR5 ≥ 0.5 kPa/L/sX5 ≤ −0.2 kPa/L/sFEV1 ≥ 80%FEV1 < 80%FEV1 ≥ 80%FEV1 < 80%FEV1 (L)2.45 (2.31-2.59) (n = 44)1.62 (1.47-1.77)∗∗∗ (n = 50)2.29 (2.10-2.47) (n = 26)1.54 (1.37-1.71)∗∗∗ (n = 38)FEF25-75 (L/s)1.92 (1.70-2.13) (n = 44)0.90 (0.75-1.05)∗∗∗ (n = 50)1.73 (1.44-2.02) (n = 26)0.84 (0.69-0.99)∗∗∗ (n = 38)FVC (L)3.31 (3.11-3.51) (n = 44)2.79 (2.55-3.04)∗∗ (n = 50)3.10 (2.88-3.33) (n = 26)2.70 (2.42-2.98)∗ (n = 38)FEV1/FVC74.0 (71.6-76.3) (n = 44)59.9 (55.9-63.9)∗∗ (n = 50)72.8 (69.8-75.8) (n = 26)59.5 (54.7-64.2)∗∗∗ (n = 38)R5 (kPa/L/s)0.68 (0.63-0.73) (n = 44)0.80 (0.72-0.88)∗ (n = 50)0.71 (0.63-0.79) (n = 26)0.83 (0.73-0.93) (n = 38)R20 (kPa/L/s)0.49 (0.46-0.52) (n = 43)0.48 (0.44-0.52) (n = 49)0.50 (0.44-0.55) (n = 26)0.48 (0.43-0.53) (n = 38)R5-R20 (kPa/L/s)0.15 (0.12-0.18) (n = 44)0.26 (0.22-0.32)∗∗∗ (n = 50)0.18 (0.13-0.23) (n = 26)0.30 (0.26-0.36)∗∗∗ (n = 38)X5 (kPa/L/s)−0.24 (−0.28 to −0.21) (n = 37)−0.42 (−0.49 to −0.35)∗∗∗ (n = 42)−0.29 (−0.32 to −0.25) (n = 26)−0.45 (−0.52 to −0.38)∗∗∗ (n = 38)AX (kPa/L)1.90 (1.46-2.34) (n = 43)4.56 (3.61-5.50)∗∗∗ (n = 48)2.50 (1.90-3.11) (n = 26)5.13 (4.06-6.20)∗∗∗ (n = 38)Fres (Hz)20.77 (18.73-22.81) (n = 41)26.20 (24.41-27.98) (n = 44)23.28 (20.63-25.94) (n = 24)27.68 (25.89-29.47)∗∗ (n = 34)FEF25-75, forced expiratory flow rate between 25% and 75% of forced vital capacity (FEF25-75%); FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.∗P < .05; ∗∗P < .01; and ∗∗∗P < .001. Open table in a new tab FEF25-75, forced expiratory flow rate between 25% and 75% of forced vital capacity (FEF25-75%); FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. ∗P < .05; ∗∗P < .01; and ∗∗∗P < .001.
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