Ventilation heterogeneity is increased in adults exposed to coal mine fire-related PM2.5.

BACKGROUND AND OBJECTIVES: The Hazelwood Health Study was set up to study long-term health effects of a mine fire that blanketed residents of the Latrobe Valley with smoke for 45 days in 2014. The Respiratory Stream specifically assessed the impact of fine particulate matter <2.5 µm diameter (PM2.5) exposure from mine fire smoke on lung health. The multiple breath nitrogen washout (MBW) test assesses ventilation heterogeneity, which may detect sub-clinical airways dysfunction not identified using standard tests such as spirometry. This analysis assessed the association of PM2.5 exposure with measures of ventilation heterogeneity. METHODS: Exposed (Morwell) and unexposed (Sale) participants were recruited 3.5-4 years after the fire from those who had participated in an Adult Survey. MBW was performed to measure lung clearance index (LCI), functional residual capacity (FRC), acinar (Sacin) and conductive (Scond) ventilation heterogeneity. PM2.5 exposure was estimated with emission and chemical transport models. Multivariable linear regression models were fitted controlling for confounders. RESULTS: We recruited 519 participants. MBW tests were conducted on 504 participants with 479 acceptable test results (40% male; 313 exposed, 166 unexposed). Exposure to mine fire-related PM2.5 was associated with increasing Scond (ß = 1.57/kL, 95%CI: 0.20-2.95, p = 0.025), which was comparable to the estimated effect on Scond of 4.7 years of aging. No other MBW outcomes were statistically different. CONCLUSION: Increasing exposure to PM2.5 was associated with increased ventilation heterogeneity in the conductive region of the lungs 4 years after the event.

Quantifying ventilation by X-ray velocimetry in healthy adults.

RATIONALE: X-ray velocimetry (XV) has been utilized in preclinical models to assess lung motion and regional ventilation, though no studies have compared XV-derived physiologic parameters to measures derived through conventional means. OBJECTIVES: To assess agreement between XV-analysis of fluoroscopic lung images and pitot tube flowmeter measures of ventilation. METHODS: XV- and pitot tube-derived ventilatory parameters were compared during tidal breathing and with bilevel-assisted breathing. Levels of agreement were assessed using the Bland-Altman analysis. Mixed models were used to characterize the association between XV- and pitot tube-derived values and optimize XV-derived values for higher ventilatory volumes. MEASUREMENTS AND MAIN RESULTS: Twenty-four healthy volunteers were assessed during tidal breathing and 11 were reassessed with increased minute ventilation with bilevel-assisted breathing. No clinically significant differences were observed between the two methods for respiratory rate (average Δ: 0.58; 95% limits of agreement: -1.55, 2.71) or duty cycle (average Δ: 0.02; 95% limits of agreement: 0.01, 0.03). Tidal volumes and flow rates measured using XV were lower than those measured using the pitot tube flowmeter, particularly at the higher volume ranges with bilevel-assisted breathing. Under these conditions, a mixed-model based adjustment was applied to the XV-derived values of tidal volume and flow rate to obtain closer agreement with the pitot tube-derived values. CONCLUSION: Radiographically obtained measures of ventilation with XV demonstrate a high degree of correlation with parameters of ventilation. If the accuracy of XV were also confirmed for assessing the regional distribution of ventilation, it would provide information that goes beyond the scope of conventional pulmonary function tests or static radiographic assessments.

Model analysis of multiple breath nitrogen washout data: robustness to variations in breathing pattern.

We recently developed a model-based method for analyzing multiple breath nitrogen washout data that does not require identification of Phase-III. In the present study, we assessed the effect of irregular breathing patterns on the intra-subject variabilities of the model parameters. Nitrogen fraction at the mouth was measured in 18 healthy and 20 asthmatic subjects during triplicate performances of multiple breath nitrogen washout, during controlled (target tidal volume 1 L at 8-12 breaths per minute) and free (unrestricted) breathing. The parameters Scond, Sacin and functional residual capacity (FRC) were obtained by conventional analysis of the slope of Phase-III. Fitting the model to the washout data provided functional residual capacity (FRCM), dead space volume (VD), the coefficient of variation of regional specific ventilation ([Formula: see text]), and the model equivalent of Sacin (Sacin-M). Intra-participant coefficients of variation for the model parameters for both health and asthma were FRCM < 5.2%, VD < 5.4%, [Formula: see text] < 9.0%, and Sacin-M < 45.6% for controlled breathing, and FRCM < 4.6%, VD < 5.3%, [Formula: see text] < 13.2%, and Sacin-M < 103.2% for free breathing. The coefficients of variation limits for conventional parameters were FRC < 6.1%, with Scond < 73.6% and Sacin < 49.2% for controlled breathing and Scond < 35.0% and Sacin < 74.4% for free breathing. The model-fitting approach to multiple breath nitrogen washout analysis provides a measure of regional ventilation heterogeneity in [Formula: see text] that is less affected by irregularities in the breathing pattern than its corresponding Phase-III slope analysis parameter Scond.

Dopamine Reverses Lung Function Deterioration After Cardiopulmonary Bypass Without Affecting Gas Exchange.

OBJECTIVE: To investigate the effects of dopamine on the adverse pulmonary changes after cardiopulmonary bypass. DESIGN: A prospective, nonrandomized clinical investigation. SETTING: A university hospital. PARTICIPANTS: One hundred fifty-seven patients who underwent elective cardiac surgery that required cardiopulmonary bypass. INTERVENTIONS: Fifty-two patients were administered intravenous infusion of dopamine (3 µg/kg/min) for five minutes after weaning from cardiopulmonary bypass; no intervention was applied in the other 105 patients. MEASUREMENTS AND MAIN RESULTS: Measurements were performed under general anesthesia and mechanical ventilation before cardiopulmonary bypass, after cardiopulmonary bypass, and after the intervention. In each protocol stage, forced oscillatory lung impedance was measured to assess airway and tissue mechanical changes. Mainstream capnography was performed to assess ventilation- and/or perfusion-matching by calculating the normalized phase-3 slopes of the time and volumetric capnograms and the physiologic deadspace. Arterial and central venous blood samples were analyzed to characterize lung oxygenation and intrapulmonary shunt. After cardiopulmonary bypass, dopamineinduced marked improvements in airway resistance and tissue damping, with relatively small decreases in lung tissue elastance. These changes were associated with decreases in the normalized phase-3 slopes of the time and volumetric capnograms. The inotrope had no effect on physiologic deadspace, intrapulmonary shunt, or lung oxygenation. CONCLUSION: Dopamine reversed the complex detrimental lung mechanical changes induced by cardiopulmonary bypass and alleviated ventilation heterogeneities without affecting the physiologic deadspace or intrapulmonary shunt. Therefore, dopamine has a potential benefit on the gas exchange abnormalities after weaning from cardiopulmonary bypass.

Ventilation heterogeneity imaged by multibreath wash-ins of hyperpolarized 3 He and 129 Xe in healthy rabbits.

KEY POINTS: Multibreath imaging to estimate regional gas mixing efficiency is superior to intensity-based single-breath ventilation markers, as it is capable of revealing minute but essential measures of ventilation heterogeneity which may be sensitive to subclinical alterations in the early stages of both obstructive and restrictive respiratory disorders. Large-scale convective stratification of ventilation in central-to-peripheral directions is the dominant feature of observed ventilation heterogeneity when imaging a heavy/less diffusive xenon gas mixture; smaller-scale patchiness, probably originating from asymmetric lung function at bronchial airway branching due to the interaction of convective and diffusive flows, is the dominant feature when imaging a lighter/more diffusive helium gas mixture. Since detecting low regional ventilation is crucial for characterizing diseased lungs, our results suggest that dilution with natural abundance helium and imaging at higher lung volumes seem advisable when imaging with hyperpolarized 129 Xe; this will allow the imaging gas to reach slow-filling and/or non-dependent lung regions, which might otherwise be impossible to distinguish from total ventilation shunt regions. The ability to differentiate these regions from those of total shunt is worse with typical single-breath imaging techniques. ABSTRACT: The mixing of freshly inhaled gas with gas already present in the lung can be directly assessed with heretofore unachievable precision via magnetic resonance imaging of signal build-up resulting from multiple wash-ins of a hyperpolarized (HP) gas. Here, we used normoxic HP 3 He and 129 Xe mixtures to study regional ventilation at different spatial scales in five healthy mechanically ventilated supine rabbits at two different inspired volumes. To decouple the respective effects of density and diffusion rates on ventilation heterogeneity, two additional studies were performed: one in which 3 He was diluted with an equal fraction of natural abundance xenon, and one in which 129 Xe was diluted with an equal fraction of 4 He. We observed systematic differences in the spatial scale of specific ventilation heterogeneity between HP 3 He and 129 Xe. We found that large-scale, central-to-peripheral convective ventilation inhomogeneity is the dominant cause of observed heterogeneity when breathing a normoxic xenon gas mixture. In contrast, small-scale ventilation heterogeneity in the form of patchiness, probably originating from asymmetric lung function at bronchial airway branching due to interactions between convective and diffusive flows, is the dominant feature when breathing a normoxic helium gas mixture, for which the critical zone occurs more proximally and at an imageable spatial scale. We also showed that the existence of particular underventilated non-dependent lung regions when breathing a heavy gas mixture is the result of the density of that mixture - rather than, for example, its diffusion rate or viscosity. Finally, we showed that gravity-dependent ventilation heterogeneity becomes substantially more uniform at higher inspired volumes for xenon gas mixtures compared to helium mixtures.

Ventilation Heterogeneity in Asthma and COPD: The Value of the Poorly Communicating Fraction as the Ratio of Total Lung Capacity to Alveolar Volume.

BACKGROUND: The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (Scond) and acinar (Sacin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement. OBJECTIVES: Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups. METHOD: We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test. RESULTS: Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and Sacin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (p < 0.05) and Sacin (p < 0.05), but not with Scond. Lastly, COPD patients with PCF >30% were highly likely to have a value ≥2 of the mMRC dyspnea scale. CONCLUSIONS: These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique.

Phenotype- and patient-specific modelling in asthma: Bronchial thermoplasty and uncertainty quantification.

Theoretical models can help to overcome experimental limitations to better our understanding of lung physiology and disease. While such efforts often begin in broad terms by determining the effect of a disease process on a relevant biological output, more narrowly defined simulations may inform clinical practice. Two such examples are phenotype-specific and patient-specific models, the former being specific to a group of patients with common characteristics, and the latter to an individual patient, in view of likely differences (heterogeneity) between patients. However, in order for such models to be useful, they must be sufficiently accurate, given the available data about the specific characteristics of the patient. We show that, for asthma in particular, this approach is promising: phenotype-specific targeting may be an effective way of selecting patients for treatment based on their airway remodelling phenotype, and patient-specific targeting may be viable with the use of a clinically-plausible dataset. Specifically we consider asthma and its treatment by bronchial thermoplasty, in which the airway smooth muscle layer is directly targeted by thermal energy. Patient-specific and phenotype-specific models in this context are considered using a combination of biobank data from ex vivo tissue samples, CT imaging, and optical coherence tomography which allows more detailed resolution of the airway wall structures.

Ventilation heterogeneity and oscillometry predict asthma control improvement following step-up inhaled therapy in uncontrolled asthma.

BACKGROUND AND OBJECTIVE: Abnormal peripheral airway function is an important feature of asthma and relates to asthma symptoms and poor asthma control. We aimed to determine whether peripheral airway function, as measured by forced oscillatory impedance and multiple-breath nitrogen washout (MBNW), relates to symptom improvement in asthmatic participants with uncontrolled asthma, after stepping up to high-dose ICS/LABA treatment. METHODS: A total of 19 subjects (14 females, mean age: 29.9 ± 13.6 years) with uncontrolled asthma, as defined by an ACQ5 > 1.5, taking 500 µg/day fluticasone equivalent or less, underwent spirometry, plethysmography, fractional exhaled FeNO, forced oscillatory resistance (Rrs5Hz ) and reactance (Xrs5Hz ), and indices of MBNW ventilation heterogeneity (lung clearance index (LCI), diffusion-convection-dependent (Sacin) and convection-dependent (Scond)). Measurements were made before and after 8 weeks of treatment with fluticasone/formoterol combination inhaler 250/10 µg, 2 puffs twice daily. RESULTS: Treatment improved ACQ5 (P = 0.0002), FEV1 (P = 0.02), FVC (P = 0.04), FeNO (P = 0.0008), Xrs5Hz (P = 0.01), LCI (P = 0.0002), Sacin (P = 0.006) and Scond (P = 0.01). At baseline, ACQ5 correlated with Xrs5Hz (rs = 0.52, P = 0.03) and Rrs5Hz (rs = 0.55, P = 0.02). The improvement in ACQ5 was predicted by more abnormal baseline LCI (P = 0.03), Scond (P = 0.02) and Rrs5Hz (P = 0.006). Baseline Scond was the best predictor of a clinically meaningful improvement in asthma control (ΔACQ > 0.5, ROC-AUC = 0.91, P = 0.007). CONCLUSION: Step-up to high-dose combination treatment in uncontrolled asthma is associated with improved peripheral airway function as measured by Xrs5Hz and MBNW. Baseline MBNW and FOT parameters correlated with the improvement in symptoms and may predict a positive response to up-titration in uncontrolled asthmatic patients.

High inspired oxygen fraction impairs lung volume and ventilation heterogeneity in healthy children: a double-blind randomised controlled trial.

BACKGROUND: Although a high inspired oxygen fraction (FiO2) is commonly used in paediatric anaesthesia, the impact on postoperative lung function is unclear. We compared lung volume, ventilation heterogeneity, and respiratory mechanics in anaesthetised children randomised to receive low or high FiO2 intraoperatively. METHODS: In a double-blind randomised controlled trial, children scheduled for elective surgery were randomly assigned FiO2 100% (n=29) or FiO2 80% (n=29) during anaesthesia induction and emergence. During maintenance of anaesthesia, participants assigned FiO2=100% at induction/emergence received FiO2=80% (FiO2>0.8 group); those randomised to FiO2=80% at induction/emergence received FiO2=35% intraoperatively (FiO2 [0.8→0.35 group]). During spontaneous breathing, we measured the (i) functional residual capacity (FRC) and lung clearance index (ventilation inhomogeneity) by multiple-breath nitrogen washout; and (ii) airway resistance and respiratory tissue elastance by forced oscillations, before operation, after discharge from the recovery room, and 24 h after operation. Mean (95% confidence intervals) are reported. RESULTS: Fifty eight children (12.9 [12.3-13.5] yr) were randomised; 22/29 (high group) and 21/29 (low group) children completed serial multiple-breath nitrogen washout measurements. FRC decreased in the FiO2>0.8 group after discharge from recovery (-12.0 [-18.5 to -5.5]%; P=0.01), but normalised 24 h later. Ventilation inhomogeneity increased in both groups after discharge from recovery, but persisted in the FiO2>0.8 group 24 h after surgery (6.1 [2.5-9.8%]%; P=0.02). Airway resistance and respiratory elastance did not differ between the groups at any time point. CONCLUSIONS: FiO2>0.8 decreases lung volume in the immediate postoperative period, accompanied by persistent ventilation inhomogeneity. These data suggest that FiO2>0.8 should be avoided in anaesthetised children with normal lungs. CLINICAL TRIAL REGISTRATION: NCT02384616.

Unraveling a Clinical Paradox: Why Does Bronchial Thermoplasty Work in Asthma?

Bronchial thermoplasty is a relatively new but seemingly effective treatment in subjects with asthma who do not respond to conventional therapy. Although the favored mechanism is ablation of the airway smooth muscle layer, because bronchial thermoplasty treats only a small number of central airways, there is ongoing debate regarding its precise method of action. Our aim in the present study was to elucidate the underlying method of action behind bronchial thermoplasty. We employed a combination of extensive human lung specimens and novel computational methods. Whole left lungs were acquired from the Prairie Provinces Fatal Asthma Study. Subjects were classified as control (n = 31), nonfatal asthma (n = 32), or fatal asthma (n = 25). Simulated lungs for each group were constructed stochastically, and flow distributions and functional indicators (e.g., resistance) were quantified both before and after a 75% reduction in airway smooth muscle in the "thermoplasty-treated" airways. Bronchial thermoplasty triggered global redistribution of clustered flow patterns wherein structural changes to the treated central airways led to a reopening cascade in the small airways and significant improvement in lung function via reduced spatial heterogeneity of flow patterns. This mechanism accounted for progressively greater efficacy of thermoplasty with both severity of asthma and degree of muscle activation, broadly consistent with existing clinical findings. We report a probable mechanism of action for bronchial thermoplasty: alteration of lung-wide flow patterns in response to structural alteration of the treated central airways. This insight could lead to improved therapy via patient-specific, tailored versions of the treatment-as well as to implications for more conventional asthma therapies.

Inter-airway structural heterogeneity interacts with dynamic heterogeneity to determine lung function and flow patterns in both asthmatic and control simulated lungs.

Asthma is a disease involving both airway remodelling (e.g. thickening of the airway wall) and acute, reversible airway narrowing driven by airway smooth muscle contraction. Both of these processes are known to be heterogeneous, and in this study we consider a new theoretical model which considers the interactions of both mechanisms: structural heterogeneity (variation in airway remodelling) and dynamic heterogeneity (emergent variation in airway narrowing and flow). By integrating both types of inter-airway heterogeneity in a full human lung geometry, we are able to draw several insights regarding the mechanisms underlying observed ventilation heterogeneity. We show that: (1) bimodal ventilation distributions are driven by paradoxical contraction/dilation patterns for airways of all sizes; (2) structural heterogeneity differences between asthmatic and control subjects significantly influences resulting lung function, and observed ventilation heterogeneity patterns; and (3) individual airway dilation probabilities are uncorrelated with prior airway remodelling of that airway.

Clinical correlates of lung ventilation defects in asthmatic children.

BACKGROUND: Lung ventilation defects identified by using hyperpolarized 3-helium gas ((3)He) lung magnetic resonance imaging (MRI) are prevalent in asthmatic patients, but the clinical importance of ventilation defects is poorly understood. OBJECTIVES: We sought to correlate the lung defect volume quantified by using (3)He MRI with clinical features in children with mild and severe asthma. METHODS: Thirty-one children with asthma (median age, 10 years; age range, 3-17 years) underwent detailed characterization and (3)He lung MRI. Quantification of the (3)He signal defined ventilation defect and hypoventilated, ventilated, and well-ventilated volumes. RESULTS: The ventilation defect to total lung volume fraction ranged from 0.1% to 11.6%. Children with ventilation defect percentages in the upper tercile were more likely to have severe asthma than children in the lower terciles (P = .005). The ventilation defect percentage correlated (P < .05 for all) positively with the inhaled corticosteroid dose, total number of controller medications, and total blood eosinophil counts and negatively with the Asthma Control Test score, FEV1 (percent predicted), FEV1/forced vital capacity ratio (percent predicted), and forced expiratory flow rate from 25% to 75% of expired volume (percent predicted). CONCLUSION: The lung defect volume percentage measured by using (3)He MRI correlates with several clinical features of asthma, including severity, symptom score, medication requirement, airway physiology, and atopic markers.

Association between peripheral airway function and neutrophilic inflammation in asthma.

BACKGROUND AND OBJECTIVE: Small airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath nitrogen washout in convection-dependent (Scond) and more peripheral diffusion-dependent (Sacin) airways. METHODS: Fifty-three (20-67 years) subjects with asthma on inhaled corticosteroid (ICS) treatment were characterized by spirometry, Scond, Sacin and induced sputum differential counts. %Predicted values for Scond and Sacin were calculated from published reference equations to adjust for the effects of age. Univariate correlations were assessed using the Spearman test. Multivariate linear regressions were performed to account for potential confounders, including age, gender, disease duration, body mass index and ICS dose. RESULTS: Sacin (%predicted) correlated significantly with neutrophil% (rs = 0.33, P = 0.02), ICS dose (rs = -0.28, P = 0.04) and age (rs = 0.27, P = 0.05). In multivariate analysis, Sacin related only to neutrophil% (adjusted R(2) = 0.18, P = 0.001). Scond (%predicted) correlated significantly only with eosinophil% (rs = 0.39, P = 0.004). There was a trend for a negative relationship with ICS dose (rs = -0.26, P = 0.06). In multivariate analysis, Scond related to eosinophil% and ICS dose independently (adjusted R(2) = 0.12, P = 0.02). CONCLUSIONS: Acinar and conductive airway dysfunction is associated with different inflammatory profiles in asthmatic airways, independently of the effects of age and disease duration. The association between acinar airway dysfunction and neutrophilic airway inflammation may have implications for asthma treatment.

Using the phase III slope of exhaled methane during a single breath DLCO test to assess ventilation heterogeneity.

BACKGROUND: The Phase III slope from a single breath nitrogen washout test provides information about ventilation heterogeneity (VH) in the lungs. PURPOSE: To determine if the Phase III slope from the exhaled tracer gas concentration during a standard, single breath DLCO test using rapid gas analysis provides similar information about VH. BASIC PROCEDURES: Retrospective analysis of clinical pulmonary function laboratory data including spirometry, lung volumes, and DLCO. The normalized Phase III slope from the exhaled CH4 concentration (SnCH4) was compared among different patterns of physiologic abnormality and with VA/TLC as an indicator of VH. MAIN FINDINGS: SnCH4 was the steepest in the group with "Obstruction and Low DLCO", with significant differences between this group and the "Normal", "Obstruction with Normal DLCO", "Mixed Obstruction and Restriction" and "Isolated Low DLCO" groups. SnCH4 was steeper in current and former smokers compared to non-smokers. Among the entire study sample, SnCH4 correlated with VA/TLC (Spearman rho = -0.56, p < 0.01) and remained a significant determinant of VA/TLC by regression modeling. PRINCIPAL CONCLUSIONS: The SnCH4 derived from a standard, single breath DLCO test using rapid gas analysis varied among distinct patterns of physiologic abnormalities and was associated with VA/TLC as a measure of VH.

Inhomogeneity of ventilation in smokers and mild COPD assessed by the ratio of alveolar volume to total lung capacity.

BACKGROUND: Previous studies have shown that the ratio between alveolar volume (VA) and total lung capacity (TLC) reflects ventilation heterogeneity in subjects with chronic obstructive pulmonary disease (COPD). However, the ratio and its correlation to respiratory symptoms had to our knowledge not previously been investigated in subjects with mild chronic airflow obstruction or without airflow obstruction (normal ratio FEV1/VC). The purpose of this study was to investigate potential connection between VA/TLC and respiratory symptoms, smoking habits and lung function parameters in subjects with normal spirometry and with mild chronic airflow obstruction. METHODS: We examined 450 subjects (82 non-smokers with normal spirometry, 298 subjects who smoked or had smoked earlier but had a normal spirometry and 70 subjects with chronical airflow obstruction) with routine lung function tests and a questionnaire regarding respiratory symptoms. RESULTS: This study showed 31 out of 54 subjects with a low VA/TLC had a normal ratio FEV1/VC. Of these subjects, 58.1 % had respiratory symptoms, compared to the group with normal ratio for both VA/TLC and FEV1/VC where 35.8 % had respiratory symptoms (p-value 0.02). CONCLUSION: This study has shown that within the group of subjects with a normal ratio FEV1/VC, those with a decreased ratio VA/TLC had a higher prevalence of respiratory symptoms compared to subjects with a normal VA/TLC ratio. These findings indicate that including the ratio VA/TLC in the evaluation of a pulmonary function test assessment might increase the possibility to identify subjects with early or at risk of lung disease.

Ventilation Heterogeneity Is a Treatable Trait in Severe Asthma.

BACKGROUND: Ventilation heterogeneity (VH) is a feature of asthma and indicates small airway disease. Nuclear imaging methods assess VH, which can facilitate clinical diagnosis and further our understanding of disease aetiology. OBJECTIVE: We sought to assess VH in severe eosinophilic asthma (SEA) using ventilation/perfusion single-photon emission computed tomography (V/P SPECT), and to assess its use as an objective test of the effect of biologic treatment for ventilation defects in SEA. METHODS: Adults (≥18 y) with severe asthma were recruited to participate in a cross-sectional observational study. Participants underwent a clinical assessment and V/P SPECT CT using Technegas as the ventilation agent. Measures were repeated for a nested before-after treatment study in people with SEA commencing biologics. RESULTS: A total of 62 participants with severe asthma were recruited. From this, 38 participants with SEA were included in the before-after study. The VH was associated with clinical variables such as lung function impairment and significantly improved after monoclonal antibody treatment in the severe asthma group. The changes in VH correlated with change in post bronchodilator forced expiratory volume in 1 second (FEV1) %predicted (r = -0.503; P = .001) and post bronchodilator FEV1/FVC (forced vital capacity) (r = -0.415; P = .01). CONCLUSIONS: The VH is clinically significant, measurable, and treatable, which establishes VH as a treatable trait in severe asthma.

Relationships of computed tomography-based small vessel indices of the lungs with ventilation heterogeneity and high transfer coefficients in non-smokers with asthma.

Background: The mechanism of high transfer coefficients of the lungs for carbon monoxide (Kco) in non-smokers with asthma is explained by the redistribution of blood flow to the area with preserved ventilation, to match the ventilation perfusion. Objectives: To examine whether ventilation heterogeneity, assessed by pulmonary function tests, is associated with computed tomography (CT)-based vascular indices and Kco in patients with asthma. Methods: Participants were enrolled from the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) study that included a prospective asthmatic cohort. Pulmonary function tests including Kco, using single breath methods; total lung capacity (TLC), using multiple breath methods; and CT, were performed on the same day. The ratio of the lung volume assessed using single breath methods (alveolar volume; VA) to that using multiple breath methods (TLC) was calculated as an index of ventilation heterogeneity. The volume of the pulmonary small vessels <5 mm2 in the whole lung (BV5 volume), and number of BV5 at a theoretical surface area of the lungs from the plural surface (BV5 number) were evaluated using chest CT images. Results: The low VA/TLC group (the lowest quartile) had significantly lower BV5 number, BV5 volume, higher BV5 volume/BV5 number, and higher Kco compared to the high VA/TLC group (the highest quartile) in 117 non-smokers, but not in 67 smokers. Multivariable analysis showed that low VA/TLC was associated with low BV5 number, after adjusting for age, sex, weight, lung volume on CT, and CT emphysema index in non-smokers (not in smokers). Conclusion: Ventilation heterogeneity may be associated with low BV5 number and high Kco in non-smokers (not in smokers). Future studies need to determine the dynamic regional system in ventilation, perfusion, and diffusion in asthma.