Reference equations for within-breath respiratory oscillometry in White adults.

BACKGROUND: within-breath analysis of oscillometry parameters is a growing research area since it increases sensitivity and specificity to respiratory pathologies and conditions. However, reference equations for these parameters in White adults are lacking and devices using multiple sinusoids or pseudorandom forcing stimuli have been underrepresented in previous studies deriving reference equations. The current study aims to establish reference ranges for oscillometry parameters, including also the within-breath ones in White adults using multi-sinusoidal oscillations. METHODS: White adults with normal spirometry, BMI≤30kg/m2, without a smoking history, respiratory symptoms, pulmonary or cardiac disease, neurological or neuromuscular disorders, and respiratory tract infections in the previous 4 weeks were eligible for the study. Study subjects underwent oscillometry (multifrequency waveform at 5-11-19Hz, Resmon PRO FULL, Restech Srl, Italy) in 5 centers in Europe and the USA according to international standards. The within-breath and total resistance (R) and reactance (X), the resonance frequency, the area under the X curve, the frequency dependence of R (R5-19), and within-breath changes of X (ΔX) were submitted to Lambda-Mu-Sigma models for deriving reference equations. For each output parameter, an AIC-based stepwise input variable selection procedure was applied. RESULTS: 144 subjects (age 20.8 - 86.3 years; height 146 - 193 cm; BMI 17.42 - 29.98 kg/m2; 56% females) were included. We derived reference equations for 29 oscillatory parameters. Predicted values for inspiratory and expiratory parameters were similar, while differences were observed for their limits of normality. CONCLUSIONS: We derived reference equations with narrow confidence intervals for within-breath and whole-breath oscillatory parameters for White adults.

Diagnostic Potential of Oscillometry: A Population-based Approach.

Rationale: Respiratory resistance (Rrs) and reactance (Xrs) as measured by oscillometry and their intrabreath changes have emerged as sensitive parameters for detecting early pathological impairments during tidal breathing. Objectives: This study evaluates the prevalence and association of abnormal oscillometry parameters with respiratory symptoms and respiratory diseases in a general adult population. Methods: A total of 7,560 subjects in the Austrian LEAD (Lung, hEart, sociAl, boDy) Study with oscillometry measurements (computed with the Resmon Pro FULL; Restech Srl) were included in this study. The presence of respiratory symptoms and doctor-diagnosed respiratory diseases was assessed using an interview-based questionnaire. Rrs and Xrs at 5 Hz, their inspiratory and expiratory components, the area above the Xrs curve, and the presence of tidal expiratory flow limitation were analyzed. Normality ranges for oscillometry parameters were defined. Measurements and Main Results: The overall prevalence of abnormal oscillometry parameters was 20%. The incidence of abnormal oscillometry increased in the presence of symptoms or diagnoses: 17% (16-18%) versus 27% (25-29%), P < 0.0001. All abnormal oscillometry parameters except Rrs at 5 Hz were significantly associated with respiratory symptoms/diseases. Significant associations were found, even in subjects with normal spirometry, with abnormal oscillometry incidence rates increasing by 6% (4-8%; P < 0.0001) in subjects with symptoms or diagnoses. Conclusions: Abnormal oscillometry parameters are present in one-fifth of this adult population and are significantly associated with respiratory symptoms and disease. Our findings underscore the potential of oscillometry as a tool for detecting and evaluating respiratory impairments, even in individuals with normal spirometry.

Role of hyperpnea in the relaxant effect of inspired CO2 on methacholine-induced bronchoconstriction.

Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in subjects with asthma (2.53 ± 0.38 cmH2O·L-1·s) than healthy subjects (2.11 ± 0.42 cmH2O·L-1·s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. V̇e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (P < 0.001) and controls (P < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in V̇e (P = 0.006 for R5 and P = 0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma.NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

Artificial intelligence for quality control of oscillometry measures.

BACKGROUND: The forced oscillation technique (FOT) allows non-invasive lung function testing during quiet breathing even without expert guidance. However, it still relies on an operator for excluding breaths with artefacts such as swallowing, glottis closure and coughing. This manual selection is operator-dependent and time-consuming. We evaluated supervised machine learning methods to exclude breaths with artefacts from data analysis automatically. METHODS: We collected 932 FOT measurements (Resmon Pro Full, Restech) from 155 patients (6-87 years) following the European Respiratory Society (ERS) technical standards. Patients were randomly assigned to either a training (70%) or test set. For each breath, we computed 71 features (including anthropometric, pressure stimulus, breathing pattern, and oscillometry data). Univariate filter, multivariate filter and wrapper methods for feature selection combined with several classification models were considered. RESULTS: Trained operators identified 4333 breaths with- and 10244 without artefacts. Features selection performed by a wrapper method combined with an AdaBoost tree model provided the best performance metrics on the test set: Balanced Accuracy = 85%; Sensitivity = 79%; Specificity = 91%; AUC-ROC = 0.93. Differences in FOT parameters computed after manual or automatic breath selection was less than ∼0.25 cmH2O*s/L for 95% of cases. CONCLUSION: Supervised machine-learning techniques allow reliable artefact detection in FOT diagnostic tests. Automating this process is fundamental for enabling FOT for home monitoring, telemedicine, and point-of-care diagnostic applications and opens new scenarios for respiratory and community medicine.

Day-to-day variability of forced oscillatory mechanics for early detection of acute exacerbations in COPD.

BACKGROUND: Telemonitoring trials for early detection of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have provided mixed results. Day-to-day variations in lung function measured by the forced oscillation technique (FOT) may yield greater insight. We evaluated the clinical utility of home telemonitoring of variability in FOT measures in terms of 1) the relationship with symptoms and quality of life (QoL); and 2) the timing of variability of FOT measures and symptom changes prior to AECOPD. METHODS: Daily FOT parameters at 5 Hz (resistance (R) and reactance (X); Resmon Pro Diary, Restech Srl, Milan, Italy), daily symptoms (COPD Assessment Test (CAT)) and 4-weekly QoL data (St George's Respiratory Questionnaire (SGRQ)) were recorded over 8-9 months from chronic obstructive pulmonary disease (COPD) patients. Variability of R and X was calculated as the standard deviation (sd) over 7-day running windows and we also examined the effect of varying window size. The relationship of FOT versus CAT and SGRQ was assessed using linear mixed modelling, daily changes in FOT variability and CAT prior to AECOPD using one-way repeated measures ANOVA. RESULTS: Fifteen participants with a mean±sd age of 69±10 years and a % predicted forced expiratory volume in 1 s (FEV1) of 39±10% had a median (interquartile range (IQR)) adherence of 95.4% (79.0-98.8%). Variability of the inspiratory component of X (indicated by the standard deviation of inspiratory reactance (SDXinsp)) related to CAT and weakly to SGRQ (fixed effect estimates 1.57, 95% CI 0.65-2.49 (p=0.001) and 4.41, 95% CI -0.06 to 8.89 (p=0.05), respectively). SDXinsp changed significantly on the same day as CAT (1 day before AECOPD, both p=0.02) and earlier when using shorter running windows (3 days before AECOPD, p=0.01; accuracy=0.72 for 5-day windows). CONCLUSIONS: SDXinsp from FOT telemonitoring reflects COPD symptoms and may be a sensitive biomarker for early detection of AECOPD.

Severity grading of chronic obstructive pulmonary disease: the confounding effect of phenotype and thoracic gas compression.

Current guidelines recommend severity of chronic obstructive pulmonary disease be graded by using forced expiratory volume in 1 s (FEV1). But this measurement is biased by thoracic gas compression depending on lung volume and airflow resistance. The aim of this study was to test the hypothesis that the effect of thoracic gas compression on FEV1 is greater in emphysema than chronic bronchitis because of larger lung volumes, and this influences severity classification and prognosis. FEV1 was simultaneously measured by spirometry and body plethysmography (FEV1-pl) in 47 subjects with dominant emphysema and 51 with dominant chronic bronchitis. Subjects with dominant emphysema had larger lung volumes, lower diffusion capacity, and lower FEV1 than those with dominant chronic bronchitis. However, FEV1-pl, patient-centered variables (dyspnea, quality of life, exercise tolerance, exacerbation frequency), arterial blood gases, and respiratory impedance were not significantly different between groups. Using FEV1-pl instead of FEV1 shifted severity distribution toward less severe classes in dominant emphysema more than chronic bronchitis. The body mass, obstruction, dyspnea, and exercise (BODE) index was significantly higher in dominant emphysema than chronic bronchitis, but this difference significantly decreased when FEV1-pl was substituted for FEV1. In conclusion, the FEV1 is biased by thoracic gas compression more in subjects with dominant emphysema than in those with chronic bronchitis. This variably and significantly affects the severity grading systems currently recommended.

Ventilation heterogeneity in obesity.

Obesity is associated with important decrements in lung volumes. Despite this, ventilation remains normally or near normally distributed at least for moderate decrements in functional residual capacity (FRC). We tested the hypothesis that this is because maximum flow increases presumably as a result of an increased lung elastic recoil. Forced expiratory flows corrected for thoracic gas compression volume, lung volumes, and forced oscillation technique at 5-11-19 Hz were measured in 133 healthy subjects with a body mass index (BMI) ranging from 18 to 50 kg/m(2). Short-term temporal variability of ventilation heterogeneity was estimated from the interquartile range of the frequency distribution of the difference in inspiratory resistance between 5 and 19 Hz (R5-19_IQR). FRC % predicted negatively correlated with BMI (r = -0.72, P < 0.001) and with an increase in slope of either maximal (r = -0.34, P < 0.01) or partial flow-volume curves (r = -0.30, P < 0.01). Together with a slight decrease in residual volume, this suggests an increased lung elastic recoil. Regression analysis of R5-19_IQR against FRC % predicted and expiratory reserve volume (ERV) yielded significantly higher correlation coefficients by nonlinear than linear fitting models (r(2) = 0.40 vs. 0.30 for FRC % predicted and r(2) = 0.28 vs. 0.19 for ERV). In conclusion, temporal variability of ventilation heterogeneities increases in obesity only when FRC falls approximately below 65% of predicted or ERV below 0.6 liters. Above these thresholds distribution is quite well preserved presumably as a result of an increase in lung recoil.

Short-term variability in respiratory impedance and effect of deep breath in asthmatic and healthy subjects with airway smooth muscle activation and unloading.

Inspiratory resistance (RINSP) and reactance (XINSP) were measured for 7 min at 5 Hz in 10 subjects with mild asymptomatic asthma and 9 healthy subjects to assess the effects of airway smooth muscle (ASM) activation by methacholine (MCh) and unloading by chest wall strapping (CWS) on the variability of lung function and the effects of deep inspiration (DI). Subjects were studied at control conditions, after MCh, with CWS, and after MCh with CWS. In all experimental conditions XINSP was significantly more negative in subjects with asthma than in healthy subjects, suggesting greater inhomogeneity in the former. However, the variability in both RINSP and XINSP was increased by either ASM activation or CWS, without significant difference between groups. DI significantly reversed MCh-induced changes in RINSP both in subjects with asthma and healthy subjects, but XINSP in the former only. This effect was impaired by CWS more in subjects with asthma than in healthy subjects. The velocity of RINSP and XINSP recovery after DI was faster in subjects with asthma than healthy subjects. In conclusion, these results support the opinion that the short-term variability in respiratory impedance is related to ASM tone or operating length, rather than to the disease. Nevertheless, ASM in individuals with asthma differs from that in healthy individuals in an increased velocity of shortening and a reduced sensitivity to mechanical stress when strain is reduced.

Mechanical correlates of dyspnea in bronchial asthma.

We hypothesized that dyspnea and its descriptors, that is, chest tightness, inspiratory effort, unrewarded inspiration, and expiratory difficulty in asthma reflect different mechanisms of airflow obstruction and their perception varies with the severity of bronchoconstriction. Eighty-three asthmatics were studied before and after inhalation of methacholine doses decreasing the 1-sec forced expiratory volume by ~15% (mild bronchoconstriction) and ~25% (moderate bronchoconstriction). Symptoms were examined as a function of changes in lung mechanics. Dyspnea increased with the severity of obstruction, mostly because of inspiratory effort and chest tightness. At mild bronchoconstriction, multivariate analysis showed that dyspnea was related to the increase in inspiratory resistance at 5 Hz (R 5) (r (2) = 0.10, P = 0.004), chest tightness to the decrease in maximal flow at 40% of control forced vital capacity, and the increase in R 5 at full lung inflation (r (2) = 0.15, P = 0.006), inspiratory effort to the temporal variability in R 5-19 (r (2) = 0.13, P = 0.003), and unrewarded inspiration to the recovery of R 5 after deep breath (r (2) = 0.07, P = 0.01). At moderate bronchoconstriction, multivariate analysis showed that dyspnea and inspiratory effort were related to the increase in temporal variability in inspiratory reactance at 5 Hz (X 5) (r (2) = 0.12, P = 0.04 and r (2) = 0.18, P < 0.001, respectively), and unrewarded inspiration to the decrease in X 5 at maximum lung inflation (r (2) = 0.07, P = 0.04). We conclude that symptom perception is partly explained by indexes of airway narrowing and loss of bronchodilatation with deep breath at low levels of bronchoconstriction, but by markers of ventilation heterogeneity and lung volume recruitment when bronchoconstriction becomes more severe.

Home monitoring of within-breath respiratory mechanics by a simple and automatic forced oscillation technique device.

Spirometry is the gold standard to determine the presence of airflow obstruction, but it requires volitional participation and needs qualified supervision. The forced oscillation technique (FOT) measures respiratory input impedance (Zrs) during spontaneous breathing and it could be useful for unsupervised monitoring of airway obstruction. We developed a FOT device for home monitoring of Zrs which transmits the data through the Internet. Its accuracy, stability and reliability were evaluated in a pilot study measuring the Zrs in the unsupervised self-measurements of five healthy subjects. Finally, to explore the applicability of the concept, 36 consecutive daily home measurements were recorded from one healthy subject and one chronic obstructive pulmonary disease (COPD) patient. The accuracy of the device fulfilled FOT guidelines, and the reliability test showed a mean discrepancy of resistance of 0.10 +/- 0.01 cmH(2)O s L(-1). The data from the healthy subjects demonstrated high repeatability in assessing Zrs. The measurements on the healthy subjects and the patient with COPD suggest the feasibility of unsupervised FOT measurements. The healthy subjects showed minimal daily variations in Zrs, whereas the patient with COPD had large differences in mean values and important fluctuations over day-to-day measurements. The results of the pilot study demonstrate that unsupervised home monitoring of Zrs using the FOT yields accurate and reproducible data. It could provide new insights into the dynamics of airway obstruction and improve the understanding and management of obstructive diseases.

Mechanical effects of obesity on airway responsiveness in otherwise healthy humans.

We investigated whether obesity is associated with airway hyperresponsiveness in otherwise healthy humans and, if so, whether this correlates with a restrictive lung function pattern or a decreased number of sighs at rest and/or during walking. Lung function was studied before and after inhaling methacholine (MCh) in 41 healthy subjects with body mass index ranging from 20 to 56. Breathing pattern was assessed during a 60-min rest period and a 30-min walk. The dose of MCh that produced a 50% decrease in the maximum expiratory flow measured in a body plethysmograph (PD50MCh) was inversely correlated with body mass index (r2=0.32, P<0.001) and waist circumference (r2=0.25, P<0.001). Significant correlations with body mass index were also found with the maximum changes in respiratory resistance (r2=0.19, P<0.001) and reactance (r2=0.40, P<0.001) measured at 5 Hz. PD50MCh was also positively correlated with functional residual capacity (r2=0.56, P<0.001) and total lung capacity (r2=0.59, P<0.001) in men, but not in women. Neither PD50MCh nor body mass index correlated with number of sighs, average tidal volume, ventilation, or breathing frequency. In this study, airway hyperresponsiveness was significantly associated with obesity in otherwise healthy subjects. In obese men, but not in women, airway hyperresponsiveness was associated with the decreases in lung volumes.