Quantification of smooth muscle in human airways by polarization-sensitive optical coherence tomography requires correction for perichondrium.

Quantifying airway smooth muscle (ASM) in patients with asthma raises the possibility of improved and personalized disease management. Endobronchial polarization-sensitive optical coherence tomography (PS-OCT) is a promising quantitative imaging approach that is in the early stages of clinical translation. To date, only animal tissues have been used to assess the accuracy of PS-OCT to quantify absolute (rather than relative) ASM in cross sections with directly matched histological cross sections as validation. We report the use of whole fresh human and pig airways to perform a detailed side-by-side qualitative and quantitative validation of PS-OCT against gold-standard histology. We matched and quantified 120 sections from five human and seven pig (small and large) airways and linked PS-OCT signatures of ASM to the tissue structural appearance in histology. Notably, we found that human cartilage perichondrium can share with ASM the properties of birefringence and circumferential alignment of fibers, making it a significant confounder for ASM detection. Measurements not corrected for perichondrium overestimated ASM content several-fold (P < 0.001, paired t test). After careful exclusion of perichondrium, we found a strong positive correlation (r = 0.96, P < 0.00001) of ASM area measured by PS-OCT and histology, supporting the method's application in human subjects. Matching human histology further indicated that PS-OCT allows conclusions on the intralayer composition and in turn potential contractile capacity of ASM bands. Together these results form a reliable basis for future clinical studies.NEW & NOTEWORTHY Polarization-sensitive optical coherence tomography (PS-OCT) may facilitate in vivo measurement of airway smooth muscle (ASM). We present a quantitative validation correlating absolute ASM area from PS-OCT to directly matched histological cross sections using human tissue. A major confounder for ASM quantification was observed and resolved: fibrous perichondrium surrounding hyaline cartilage in human airways presents a PS-OCT signature similar to ASM for birefringence and optic axis orientation. Findings impact the development of automated methods for ASM segmentation.

Long-term impact of coal mine fire smoke on lung mechanics in exposed adults.

BACKGROUND AND OBJECTIVE: In 2014, a 6-week-long fire at the Hazelwood coal mine exposed residents in the adjacent town of Morwell to high concentrations of fine particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5 ). The long-term health consequences are being evaluated as part of the Hazelwood Health Study. METHODS: Approximately 3.5-4 years after the mine fire, adults from Morwell (n = 346) and the comparison town Sale (n = 173) participated in the longitudinal Respiratory Stream of the Study. Individual PM2.5 exposure was retrospectively modelled. Lung mechanics were assessed using the forced oscillation technique (FOT), utilizing pressure waves to measure respiratory system resistance (Rrs) and reactance (Xrs). Multivariate linear regression was used to evaluate associations between PM2.5 and transformed Rrs at 5 Hz, area under the reactance curve (AX5) and Xrs at 5 Hz controlling for key confounders. RESULTS: There were clear dose-response relationships between increasing mine fire PM2.5 and worsening lung mechanics, including a reduction in post-bronchodilator (BD) Xrs5 and an increase in AX5. A 10 µg/m3 increase in mine fire-related PM2.5 was associated with a 0.015 (95% CI: 0.004, 0.027) reduction in exponential (Xrs5) post-BD, which was comparable to 4.7 years of ageing. Similarly, the effect of exposure was associated with a 0.072 (0.005, 0.138) increase in natural log (lnAX5) post-BD, equivalent to 3.9 years of ageing. CONCLUSION: This is the first study using FOT in adults evaluating long-term respiratory outcomes after medium-term ambient PM2.5 exposure to coal mine fire smoke. These results should inform public health policies and planning for future events.

Exercise oscillatory ventilation during autonomic blockade in young athletes and healthy controls.

PURPOSE: Exercise oscillatory ventilation (EOV) is a form of periodic breathing that is associated with a poor prognosis in heart failure patients, but little is known about EOV in other populations. We sought to provide insights into the phenomenon of EOV after it was observed in young healthy subjects, including athletes, after the administration of dual autonomic blockade (DAB). METHODS: From 29 participants who completed cardiopulmonary exercise testing (CPET) with and without DAB (0.04 mg/kg atropine and 0.2 mg/kg metoprolol), 5 subjects developed EOV (age = 29 ± 5 years; 3/5 were athletes) according to American Heart Association criteria. For each case, we identified 2 non-EOV healthy controls (age = 34.2 ± 8.3; 7/10 were athletes) that were subsequently age- and sex-matched. RESULTS: No participants had EOV during exercise without DAB. The 5 participants (4 male, 1 female) who demonstrated EOV with DAB had lower mean tidal volume (1.7 ± 0.5 L/min vs. 1.8 ± 0.5 L/min; p = 0.04) compared to participants in the non-EOV group and a decrease in peak tidal volume (2.9 ± 0.6 L/min to 2.2 ± 0.7 L/min; p = 0.004) with DAB. There were few other differences in CPET measures between EOV and non-EOV participants, although the PETCO2 tended to be higher in the EOV group (p = 0.07). CONCLUSION: EOV can be elucidated in young healthy subjects, including athletes, during cardiopulmonary exercise testing, suggesting that it may not be an ominous sign in all populations.

Increased Dead Space Ventilation Mediates Reduced Exercise Capacity in Systolic Heart Failure.

RATIONALE: Patients with chronic heart failure have limited exercise capacity, which cannot be completely explained by markers of cardiac dysfunction. Reduced pulmonary diffusing capacity at rest and excessively high ventilation during exercise are common in heart failure. We hypothesized that the reduced pulmonary diffusing capacity in patients with heart failure would predict greater dead space ventilation during exercise and that this would lead to impairment in exercise capacity. OBJECTIVES: To determine the relationship between pulmonary diffusing capacity at rest and dead space ventilation during exercise, and to examine the influence of dead space ventilation on exercise in heart failure. METHODS: We analyzed detailed cardiac and pulmonary data at rest and during maximal incremental cardiopulmonary exercise testing from 87 consecutive heart transplant assessment patients and 18 healthy control subjects. Dead space ventilation was calculated using the Bohr equation. MEASUREMENTS AND MAIN RESULTS: Pulmonary diffusing capacity at rest was a significant predictor of dead space ventilation at maximal exercise (r = -0.524, P < 0.001) in heart failure but not in control subjects. Dead space at maximal exercise also correlated inversely with peak oxygen consumption (r = -0.598, P < 0.001), peak oxygen consumption per kilogram (r = -0.474, P < 0.001), and 6-minute-walk distance (r = -0.317, P = 0.021) in the heart failure group but not in control subjects. CONCLUSIONS: Low resting pulmonary diffusing capacity in heart failure is indicative of high dead space ventilation during exercise, leading to excessive and inefficient ventilation. These findings would support the concept of pulmonary vasculopathy leading to altered ventilation perfusion matching (increased dead space) and resultant dyspnea, independent of markers of cardiac function.

Improving asthma outcomes: Clinicians' perspectives on peripheral airways.

Disease of the peripheral (or small) airways is fundamental in asthma, being closely related to symptoms (or lack of control of them), airway hyperresponsiveness, spirometric abnormalities, risk of loss of control, or exacerbations and inflammation. Current technology now allows routine measurement of peripheral airway function. Having a working concept of peripheral airways disease in asthma is arguably very useful to clinicians and beneficial to patients because it allows a more comprehensive assessment of asthma severity (rather than just symptoms alone, which is the norm), tracking of progress or deterioration, and assessing response to treatment. Oscillometry is a sensitive way to monitor the peripheral airways, whereas multiple breath nitrogen washout parameters are excellent measures of future risk. In the longer term, physiologic measurements will be crucial in research to define causes and find new disease-modifying treatments.

Airway oscillometry parameters in baseline lung allograft dysfunction: Associations from a multicenter study.

BACKGROUND: Baseline lung allograft dysfunction (BLAD), the failure to achieve ≥80%-predicted spirometry after lung transplant (LTx), is associated with impaired survival. Physiologic abnormalities in BLAD are poorly understood. Airway oscillometry measures respiratory system mechanics and may provide insight into understanding the mechanisms of BLAD. OBJECTIVES: This study aims to describe and measure the association between airway oscillometry parameters [Reactance (Xrs5, Ax), Resistance (Rrs5, Rrs5-19)] (1) stable LTx recipients, comparing those with normal spirometry and those with BLAD; and (2) in recipients with chronic lung allograft dysfunction (CLAD), comparing those with normal baseline spirometry and those with BLAD. METHODS: A multi-center cross-sectional study was performed including bilateral LTx between January 2020 and June 2021. Participants performed concurrent airway oscillometry and spirometry. Multivariable logistic regression was performed to measure the association between oscillometry parameters and BLAD. RESULTS: A total of 404 LTx recipients performed oscillometry and 253 were included for analysis. Stable allograft function was confirmed in 149 (50.2%) recipients (92 (61.7%) achieving normal spirometry and 57 (38.3%) with BLAD). Among stable LTx recipients, lower Xrs5 Z-Score (aOR 0.50 95% CI 0.37-0.76, p = 0.001) was independently associated with BLAD. CLAD was present in 104 (35.0%) recipients. Among recipients with CLAD, lower Xrs5 Z-Score (aOR 0.73 95% CI 0.56-0.95, p = 0.02) was associated with BLAD. CONCLUSIONS: Oscillometry provides novel physiologic insights into mechanisms of BLAD. The independent association between Xrs5 and BLAD, in both stable recipients and those with CLAD suggests that respiratory mechanics, in particular abnormal elastance, is an important physiologic feature. Further longitudinal studies are needed to understand the trajectory of oscillometry parameters in relation to allograft outcomes.

Small airways dysfunction is associated with increased exacerbations in patients with asthma.

There is a poor understanding of why some patients with asthma experience recurrent exacerbations despite high levels of treatment. We compared measurements of peripheral ventilation heterogeneity and respiratory system mechanics in participants with asthma who were differentiated according to exacerbation history, to ascertain whether peripheral airway dysfunction was related to exacerbations. Three asthmatic groups: "stable" (no exacerbations for >12 mo, n = 18), "exacerbation-prone" (≥1 exacerbation requiring systemic corticosteroids within the last 12 mo, but stable for ≥1-mo, n = 9), and "treated-exacerbation" (exacerbation requiring systemic corticosteroids within the last 1 mo, n = 12) were studied. All participants were current nonsmokers with <10 pack yr smoking history. Spirometry, static lung volumes, ventilation heterogeneity from multibreath nitrogen washout (MBNW), and respiratory system mechanics from oscillometry were measured. The exacerbation-prone group compared with the stable group had slightly worse spirometry [forced expired volume in 1 s or FEV1 z-score -3.58(1.13) vs. -2.32(1.06), P = 0.03]; however, acinar ventilation heterogeneity [Sacin z-score 7.43(8.59) vs. 3.63(3.88), P = 0.006] and respiratory system reactance [Xrs cmH2O·s·L-1 -2.74(3.82) vs. -1.32(1.94), P = 0.01] were much worse in this group. The treated-exacerbation group had worse spirometry but similar small airway function, compared with the stable group. Patients with asthma who exacerbate have worse small airway function as evidenced by increases in Sacin measured by MBNW and ΔXrs from oscillometry, both markers of small airway dysfunction, compared with those that do not.NEW & NOTEWORTHY This study assessed the relationship between peripheral airway function, measured by multiple breath nitrogen washout and oscillometry impedance, and exacerbation history. We found that those with a history of exacerbation in the last year had worse peripheral airway function, whereas those recently treated for an asthma exacerbation had peripheral airway function that was comparable to the stable group. These findings implicate active peripheral airway dysfunction in the pathophysiology of an asthma exacerbation.

Airway closure is the predominant physiological mechanism of low ventilation seen on hyperpolarized helium-3 MRI lung scans.

Hyperpolarized helium-3 MRI (3He MRI) provides detailed visualization of low- (hypo- and non-) ventilated lungs. Physiological measures of gas mixing may be assessed by multiple breath nitrogen washout (MBNW) and of airway closure by a forced oscillation technique (FOT). We hypothesize that in patients with asthma, areas of low-ventilated lung on 3He MRI are the result of airway closure. Ten control subjects, ten asthma subjects with normal spirometry (non-obstructed), and ten asthmatic subjects with reduced baseline lung function (obstructed) attended two testing sessions. On visit one, baseline plethysmography was performed followed by spirometry, MBNW, and FOT assessment pre and post methacholine challenge. On visit two, 3He MRI scans were conducted pre and post methacholine challenge. Post methacholine the volume of low-ventilated lung increased from 8.3% to 13.8% in the non-obstructed group (P = 0.012) and from 13.0% to 23.1% in the obstructed group (P = 0.001). For all subjects, the volume of low ventilation from 3He MRI correlated with a marker of airway closure in obstructive subjects, Xrs (6 Hz) and the marker of ventilation heterogeneity Scond with r2 values of 0.61 (P < 0.001) and 0.56 (P < 0.001), respectively. The change in Xrs (6 Hz) correlated well (r2 = 0.45, p < 0.001), whereas the change in Scond was largely independent of the change in low ventilation volume (r2 = 0.13, P < 0.01). The only significant predictor of low ventilation volume from the multi-variate analysis was Xrs (6 Hz). This is consistent with the concept that regions of poor or absent ventilation seen on 3He MRI are primarily the result of airway closure.NEW & NOTEWORTHY This study introduces a novel technique of generating high-resolution 3D ventilation maps from hyperpolarized helium-3 MRI. It is the first study to demonstrate that regions of poor or absent ventilation seen on 3He MRI are primarily the result of airway closure.

Early onset of airway derecruitment assessed using the forced oscillation technique in subjects with asthma.

Derecruitment of air spaces in the lung occurs when airways close during exhalation and is related to ventilation heterogeneity and symptoms in asthma. The forced oscillation technique has been used to identify surrogate measures of airway closure via the reactance (Xrs) versus lung volume relationship. This study used a new algorithm to identify derecruitment from the Xrs versus lung volume relationship from a slow vital capacity maneuver. We aimed to compare two derecruitment markers on the Xrs versus volume curve, the onset reduction of Xrs (DR1vol) and the onset of more rapid reduction of Xrs (DR2vol), between control and asthmatic subjects. We hypothesized that the onset of DR1vol and DR2vol occurred at higher lung volume in asthmatic subjects. DR1vol and DR2vol were measured in 18 subjects with asthma and 18 healthy controls, and their relationships with age and height were examined using linear regression. In the control group, DR1vol and DR2vol increased with age (r2 = 0.68, P < 0.001 and r2 = 0.71, P < 0.001, respectively). DR1vol and DR2vol in subjects with asthma [76.58% of total lung capacity (TLC) and 56.79%TLC, respectively] were at higher lung volume compared with control subjects (46.1 and 37.69%TLC, respectively) (P < 0.001). DR2vol correlated with predicted values of closing capacity (r = 0.94, P < 0.001). This study demonstrates that derecruitment occurs at two points along the Xrs-volume relationship. Both derecruitment points occurred at significantly higher lung volumes in subjects with asthma compared with healthy control subjects. This technique offers a novel way to measure the effects of changes in airways/lung mechanics. NEW & NOTEWORTHY This study demonstrates that the forced oscillation technique can be used to identify two lung volume points where lung derecruitment occurs: 1) where derecruitment is initiated and 2) where onset of rapid derecruitment commences. Measurements of derecruitment increase with age. The onset of rapid derecruitment was highly correlated with predicted closing capacity. Also, the initiation and rate of derecruitment are significantly altered in subjects with asthma.

Ventilation heterogeneity is increased in patients with chronic heart failure.

In the healthy lung, ventilation is distributed heterogeneously due to factors such as anatomical asymmetry and gravity. This ventilation heterogeneity increases pathologically in conditions such as asthma, chronic obstructive lung disease, and cystic fibrosis. In chronic heart failure, lung biopsy demonstrates evidence of peripheral lung fibrosis and small airways narrowing and distortion. We hypothesized that this would lead to increased ventilation heterogeneity. Furthermore, we proposed that rostral fluid shifts when seated patients lie supine would further increase ventilation heterogeneity. We recruited 30 ambulatory chronic heart failure patients (57 ± 10 years, 83% male, left ventricular ejection fraction 31 ± 12%) as well as 10 healthy controls (51 ± 13 years, 90% male). Heart failure patients were clinically euvolemic. Subjects underwent measurement of ventilation heterogeneity using the multiple-breath nitrogen washout technique in the seated position, followed by repeat measurements after 5 and 45 min in the supine position. Ventilation heterogeneity was calculated using the lung clearance index (LCI), Sacin and Scond which represent overall, acinar, and small conducting airway function, respectively. Lung clearance index (9.6 ± 1.2 vs. 8.6 ± 1.4 lung turnovers, P = 0.034) and Scond (0.029 ± 0.014 vs. 0.006 ± 0.016/L, P = 0.007) were higher in the heart failure patients. There was no difference in Sacin (0.197 ± 0.171 vs. 0.125 ± 0.081/L, P = 0.214). Measures of ventilation heterogeneity did not change in the supine position. This study confirms the presence of peripheral airway pathology in patients with chronic heart failure. This leads to subtle but detectable functional abnormalities which do not change after 45 min in the supine position.

Variations in the accuracy of the ECG based detection of obstructive sleep apnoea (OSA) for different numbers of ECG leads and categories of OSA events.

This study investigates the finding that there is a more pronounced change to ECG physiological predictors during apnoea events compared to hypopnoea events and therefore accurate detection of hypopnoea events is likely to be more challenging than detection of apnoea events. The relevant statistical analysis was conducted by generating logistic regression models from the two data sets: the first one containing only the apnoea events and controls and the second data set containing only the hypopnoea events and controls. The discriminating ability of the model from the apnoea data set (AUC = 0.903, CI = 0.888 - 0.920) was significantly superior compared to the model from the hypopnoea data set (AUC = 0.842, CI = 0.817-0.866). The second study objective investigated whether regression models comprising the OSA predictors derived from the two ECG signals performed better than models that involved parameters of a single ECG. The optimised two signal ECG model (AUC = 0.878 and CI = 0.864 - 0.893) outperformed the best single ECG model (AUC = 0.843, CI = 0.826 - 0.860), suggesting that improved results can be achieved using an additional ECG lead.