Plamen Bokov

Relationships between Specific Airway Resistance and Forced Expiratory Flows in Asthmatic Children

Background The earliest changes associated with airflow obstruction in asthmatic children are a proportionally greater reduction in FEF50% than in FEV1 using spirometry, and an increase in specific airway resistance (sRaw) using body plethysmography. Consequently, we hypothesized that sRaw could be better linked to FEF50% than to FEV1. The first aim was to assess the relationships between forced expiratory flows and sRaw in a large group of asthmatic children in a transversal study. We then performed a longitudinal study in order to determine whether sRaw of preschool children could predict subsequent impairment of forced expiratory flows at school age. Methodology Pulmonary function tests (sRaw and forced expiratory flows) of 2193 asthmatic children were selected for a transversal analysis, while 365 children were retrospectively selected for longitudinal assessment from preschool to school age. Principal Findings The transversal data showed that sRaw is differently related to FEF50% (−1/sRaw) and to FEV1 (near linearly). These results were further explained by a simple one-compartment lung model, which justified the shape of the observed relationships. As hypothesized, sRaw correlated more strongly to FEF50% than to FEV1 (r = −0.64 versus −0.39, respectively; p<0.001). In the longitudinal part of the study, sRaw at preschool age correlated with subsequent FEF50% (% predicted) (−0.31, 95% CI, −0.40 to −0.22), but weakly with subsequent FEV1 (% predicted) (−0.09, 95% CI, −0.20 to 0). Conclusion Specific Raw is more strongly related to FEF50% than to FEV1 and could be used in preschool children to predict subsequent mild airflow limitation.

Use of specific airway resistance to assess bronchodilator response in children

Background and objective:  Changes in specific airway resistance (ΔsRaw) after bronchodilation, as measured by plethysmography and FEV1, are frequently considered to be interchangeable indices of airway obstruction. However, the baseline relationship between these two indices is weak, and the value of ΔsRaw that best predicts FEV1 reversibility in children has yet to be determined. The aim of this study was (i) to establish the sRaw cut‐off value that best distinguishes between positive and negative bronchodilator responses, as measured by FEV1 reversibility; (ii) to determine whether the discrepancy between ΔsRaw and ΔFEV1 might be explained by independent correlations between ΔFEV1 and both ΔsRaw (mainly airway obstruction) and ΔFVC (airway closure); and (iii) to assess the effect of height and age on the relationship between ΔsRaw and ΔFEV1.

Lumen areas and homothety factor influence airway resistance in COPD

The remodelling process of COPD may affect both airway calibre and the homothety factor, which is a constant parameter describing the reduction of airway lumen (h(d): diameter of child/parent bronchus) that might be critical because its reduction would induce a frank increase in airway resistance. Airway dimensions were obtained from CT scan images of smokers with (n=22) and without COPD (n=9), and airway resistance from plethysmography. Inspiratory airway resistance correlated to lumen area of the sixth bronchial generation of right lung, while peak expiratory flow correlated to the area of the third right generation (p=0.0009, R=0.57). A significant relationship was observed between h(d) and resistance (p=0.036; R(2)=0.14). A modelling approach of central airways (5 generations) further described the latter relationship. In conclusion, a constant homothety factor can be described by CT scan analysis, which partially explains inspiratory resistance, as predicted by theoretical arguments. Airway resistance is related to lumen areas of less proximal airways than commonly admitted.

Gas trapping is associated with severe exacerbation in asthmatic children.

BACKGROUND Gas trapping suggesting small airway disease is observed in adult asthmatic suffering from severe asthma. The aim of the study was to assess whether gas trapping could be evidenced in asthmatic children with/without severe exacerbation and with/without symptoms during the past three months. METHODS AND PATIENTS Forced expiratory flows (FEV(1), FVC, MEF(25-75%), MEF(50%)), plethysmographic lung volumes (TLC, FRC, RV) before and after bronchodilation (BD) were recorded in asthmatic children with documented airflow reversibility. Three groups were defined according to the presence during the last three months of 1) severe exacerbation (oral steroid: 3 consecutive days) 2) asthma symptoms without severe exacerbation and 3) without any symptom (GINA guidelines). RESULTS 180 children (median 11.3 years, range 6.3-17.6, 57 girls) were included, 24 (13%) had at least one severe exacerbation, 58 (33%) had respiratory symptoms without severe exacerbation and 98 (54%) had no symptom during the past 3 months. Forced expiratory flows did not significantly differ in these three groups, while RV/TLC was significantly higher in the first group before and even after bronchodilation: before BD, 0.27 +/- 0.07, 0.24 +/- 0.05 and 0.23 +/- 0.05, respectively (p = 0.016) and after BD, 0.25 +/- 0.07, 0.21 +/- 0.05, 0.21 +/- 0.05, respectively (p = 0.003). CONCLUSION In asthmatic children, gas trapping is associated with occurrence of a severe exacerbation during the last three months, suggesting a small airway disease that is not evidenced by forced expiratory flows.

Abnormalities of plethysmographic lung volumes in asthmatic children

BACKGROUND While lung hyperinflation is frequent in asthma, measurement of lung volumes is not recommended in current guidelines. The aim of this descriptive functional study was to assess whether systematic measurement of volumes by plethysmography may detect isolated hyperinflation with normal expiratory flows. METHODS AND PATIENTS One hundred sixty asthmatic children (mean age + or - SD: 10.8 + or - 2.7 years; 50 girls) receiving inhaled corticosteroid underwent lung function tests before and after bronchodilation (BD). To avoid the problem of dysanaptic lung growth on predicted values in childhood, airflow limitation and hyperinflation were defined by ratios (FEV(1,%pred)/FVC(%pred) for the former, RV/TLC for the latter) and values below and above the 5th or 95th percentiles of reference values, were chosen as cut-off values. RESULTS Different functional phenotypes were evidenced, mainly normal lung function (142/160 [89%] after BD), but also isolated airflow limitation (35/160 [22%] before and 7/160 [4%] after BD) and isolated hyperinflation (17/160 [11%] before and 11/160 [7%] after BD), while the combination of both impairments before BD (13/160 [8%]) was never observed after BD. There was no statistical relationship between airflow limitation and hyperinflation, either before or after BD. Indices of spirometry (FEV(1), FEF(50%)) were unable to predict isolated hyperinflation that corresponds to small airway obstructive syndrome. CONCLUSION Isolated hyperinflation is not infrequent in asthmatic children (7-11%) and small airway obstruction is not detected by forced expiratory flows.

Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease.

Background The aims of the study were: (1) to compare numerical parameters of specific airway resistance (total, sRawtot, effective, sRaweff and at 0.5 L · s−1, sRaw0.5) and indices obtained from the forced oscillation technique (FOT: resistance extrapolated at 0 Hz [Rrs0 Hz], mean resistance [Rrsmean], and resistance/frequency slope [Rrsslope]) and (2) to assess their relationships with dyspnea in chronic obstructive pulmonary disease (COPD). Methods A specific statistical approach, principal component analysis that also allows graphic representation of all correlations between functional parameters was used. A total of 108 patients (mean ± SD age: 65 ± 9 years, 31 women; GOLD stages: I, 14; II, 47; III, 39 and IV, 8) underwent spirometry, body plethysmography, FOT, and Medical Research Council (MRC) scale assessments. Results Principal component analysis determined that the functional parameters were described by three independent dimensions (airway caliber, lung volumes and their combination, specific resistance) and that resistance parameters of the two techniques were not equivalent, obviously. Correlative analyses further showed that Rawtot and Raweff (and their specific resistances) can be considered as equivalent and correlated with indices that are considered to explore peripheral airways (residual volume (RV), RV/ total lung capacity (TLC), Rrsslope), while Rrsmean and Raw0.5 explored more central airways. Only specific resistances taking into account the specific resistance loop area (sRawtot and sRaweff) and Rrsslope were statistically linked to dyspnea. Conclusion Parameters obtained from both body plethysmography and FOT can explore peripheral airways, and some of these parameters (sRawtot, sRaweff, and Rrsslope) are linked to activity-related dyspnea in moderate to severe COPD patients.

Correction of carotid intima-media thickness for adaptive dependence on tensile stress: implication for cardiovascular risk assessment.

Early artery wall‐thickening detected by ultrasound‐assessed increased carotid intima‐media thickness (IMT) may reflect atherosclerosis or represent an adaptive response to keep homeostasis tensile stress that is related inversely to wall thickness by Laplaces equation. We attempted to discriminate between both mechanisms by correcting IMT for its inverse association with tensile stress.

Lung Function Impairment Evidenced by Sequential Specific Airway Resistance in Childhood Persistent Asthma: A Longitudinal Study

Background. Specific airway resistance (sRaw) is virtually independent of lung growth, height, and gender, thus facilitating longitudinal follow-up. Objective. To assess whether a specific phenotype of asthmatic children with a decline in lung function can be evidenced using sRaw. Methods. The authors hypothesized that sequential sRaw measurements over a long period would detect subtle trends. Clinical and functional data of children with persistent asthma under inhaled corticosteroids, evaluated at least three times per year for at least 4 years, were retrieved from a database. Results. One hundred fourteen children (30 girls) were followed for (median [interquartile range]) 6.9 years [5.6–7.9]. Data from 1699 measurements of sRaw (median 14/child) allowed the calculation of individual slopes of sRaw plotted against time demonstrating stable values in the group as a whole between 4 and 18 years. A positive correlation between individual slopes and the degree of intraindividual variation of sRaw was observed (R2 = .16; p < .0001). Children with more than one positive skin test showed larger intrasubject variation of sRaw (p = .011). In 19/114 children (17%), a significant increase in sRaw of 12.3% per year (median) was observed. As compared to children without, those with a significant increase in sRaw were boys (p < .0001), had a lower initial (p = .008) and a higher final resistance (p = .025) but did not differ in terms of inhaled corticosteroid dose. Conclusion. This retrospective study identifies a specific phenotype of asthmatic children that develops an impairment of lung function, confirming the results of a post hoc analysis of the Childhood Asthma Management Program study.

Increased ventilatory variability and complexity in patients with hyperventilation disorder

It has been hypothesized that hyperventilation disorders could be characterized by an abnormal ventilatory control leading to enhanced variability of resting ventilation. The variability of tidal volume (VT) often depicts a nonnormal distribution that can be described by the negative slope characterizing augmented breaths formed by the relationship between the probability density distribution of VT and VT on a log-log scale. The objectives of this study were to describe the variability of resting ventilation [coefficient of variation (CV) of VT and slope], the stability in respiratory control (loop, controller and plant gains characterizing ventilatory-chemoresponsiveness interactions) and the chaotic-like dynamics (embedding dimension, Kappa values characterizing complexity) of resting ventilation in patients with a well-defined dysfunctional breathing pattern characterized by air hunger and constantly decreased PaCO2 during a cardiopulmonary exercise test. Compared with 14 healthy subjects with similar anthropometrics, 23 patients with hyperventilation were characterized by increased variability of resting tidal ventilation (CV of VT median [interquartile]: 26% [19-35] vs. 36% [28-48], P = 0.020; slope: -6.63 [-7.65; -5.36] vs. -3.88 [-5.91; -2.66], P = 0.004) that was not related to increased chemical drive (loop gain: 0.051 [0.039-0.221] vs. 0.044 [0.012-0.087], P = 0.149) but that was related to an increased ventilatory complexity (Kappa values, P < 0.05). Plant gain was decreased in patients and correlated with complexity (with Kappa 5 - degree 5: Rho = -0.48, P = 0.006). In conclusion, well-defined patients suffering from hyperventilation disorder are characterized by increased variability of their resting ventilation due to increased ventilatory complexity with stable ventilatory-chemoresponsiveness interactions.

Homothety ratio of airway diameters and site of airway resistance in healthy and COPD subjects.

Our objective was to evaluate whether a decrease in the homothety ratio (h: diameter of child/parent bronchus, constant over generations) explains the shift in airway resistance toward periphery in chronic obstructive pulmonary disease (COPD). Using a validated computational model of fluid motion, we determined that reduced values of h (<0.76) were associated with a shift in resistance toward periphery. The calculated luminal diameters of terminal bronchioles using normal h (0.80-0.85) or reduced h (0.70-0.75) fitted well with measured micro-CT values obtained by McDonough et al. (N. Engl. J. Med., 2011; 365:1567-75) in control and COPD patients, respectively. A semi-analytic formula of resistance using tracheal dimensions and h was developed, and using experimental data (tracheal area and h from patients [Bokov et al., Respir. Physiol. Neurobiol., 2010; 173:1-10]), we verified the agreement between measured and calculated resistance (r=0.42). In conclusion, the remodeling process of COPD may reduce h and explain the shift in resistance toward lung periphery.