Multiple Breath Washout Indices Research Articles

Multiple breath washout and oscillometry after allogenic HSCT: a scoping review.

Pulmonary chronic graft-versus-host disease (cGVHD) is a substantial cause of pulmonary morbidity and mortality post-haematopoietic stem cell transplantation (HSCT). Current spirometry-based monitoring strategies have significant limitations. Understanding the utility of novel peripheral airway function tests - multiple breath washout (MBW) and oscillometry - is critical in efforts to improve detection, facilitate earlier intervention and improve outcomes. In this scoping review, we identified 17 studies investigating MBW or oscillometry, or both, after allogenic HSCT. Despite small study numbers limiting the ability to draw firm conclusions, several themes were evident. Detectable peripheral airway abnormality in MBW occurred in a substantial proportion prior to HSCT. MBW indices post-HSCT were more frequently abnormal than spirometry when reporting group data and among those with extrapulmonary cGVHD and pulmonary cGVHD. Changes in MBW indices over time may be more indicative of pulmonary complications than absolute values at any given time point. Oscillometry indices were often normal at baseline, but more frequently abnormal in those who developed pulmonary cGVHD. Pooling currently available individual participant data across these studies may improve our ability to formally compare their respective sensitivity and specificity at specific time points and assess the trajectory of MBW and oscillometry indices over time.

Multiple breath washout: measuring early manifestations of lung pathology.

The multiple breath washout (MBW) test measures the efficiency of gas mixing in the lungs and has gained significant interest over the past 20 years. MBW outcomes detect early lung function impairment and peripheral airway pathology, through its main outcome measure lung clearance index (LCI). LCI measures the number of lung turnovers required to washout an inert tracer gas. MBW is performed during normal (tidal) breathing, making it particularly suitable for young children or those who have trouble performing forced manoeuvres. Additionally, research in chronic respiratory disease populations has shown that MBW can detect acute clinically relevant changes before conventional lung function tests, such as spirometry, thus enabling early intervention. The development of technical standards for MBW and commercial devices have allowed MBW to be implemented in clinical research and potentially routine clinical practice. Although studies have summarised clinimetric properties of MBW indices, additional research is required to establish the clinical utility of MBW and, if possible, shorten testing time. Sensitive, feasible measures of early lung function decline will play an important role in early intervention for people living with respiratory diseases.Educational aimTo describe the multiple breath washout test, its applications to lung pathology and respiratory disease, as well as directions for future research.

Ventilation efficiency to exercise in patients with cystic fibrosis.

Exercise ventilation efficiency index in cardiopulmonary exercise testing (CPET) is elevated in patients with heart failure providing useful information on disease progression and prognosis. Few data, however, exist for ventilation efficiency index among cystic fibrosis (CF) patients. To assess ventilation efficiency index (ΔVE/ΔVCO2 or V'E/V'CO2 slope) and intercept of ventilation (VE-intercept) in CF patients with mild, moderate, and severe cystic fibrosis (CF) lung disease. To assess possible correlations with ventilation inhomogeneity and structural damages as seen on high resolution computed tomography (HRCT). CF patients with mild (FEV1 > 80%, n = 47), moderate (60% < FEV1 < 80%, n = 21), and severe (FEV1 < 60%, n = 9) lung disease, mean age 14.9 years participated. Peak oxygen uptake (VO2 peak), pulmonary ventilation at peak exercise (VE), respiratory equivalent ratios for oxygen and carbon dioxide at peak exercise (VE/VO2 , VE/VCO2 ), end-tidal CO2 (PetCO2 ), and ΔVE/ΔVCO2 , ΔVE/ΔVO2 in a maximal CPET along with spirometry and multiple breath washout indices were examined. HRCT scans were performed and scored using Bhalla score. Mean ΔVE/ΔVCO2 showed no significant differences among the three groups (P = .503). Mean VEint discriminated significantly among the different groups (p 2 < 0.001). Ventilation efficiency index did not correlate either with LCI or Bhalla score. However, VE together with ΔVE/ΔVCO2 slope could predict Bhalla score (r 2 = 0.869, P = .006). No significant differences were found regarding ΔVE/ΔVCO2 slope levels between the three groups. Ventilation intercept (VEint ) was elevated significantly as disease progresses reflecting increased dead space ventilation. CF patients retain their ventilation efficiency to exercise even as lung function deteriorates by adopting a higher respiratory rate along with increased dead space ventilation.

Single-breath washout and association with structural lung disease in children with cystic fibrosis.

In children with cystic fibrosis (CF) lung clearance index (LCI) from multiple-breath washout (MBW) correlates with structural lung disease. As a shorter test, single-breath washout (SBW) represents an attractive alternative to assess the ventilation distribution, however, data for the correlation with lung imaging are lacking. We assessed correlations between phase III slope (SIII) of double-tracer gas SBW, nitrogen MBW indices (LCI and moment ratios for overall ventilation distribution, Scond, and Sacin for conductive and mainly acinar ventilation, respectively) and structural lung disease assessed by chest computed tomography (CT) in children with CF. In a prospective cross-sectional study data from MBW, SBW, and chest CT were obtained in 32 children with CF with a median (range) age of 8.2 (5.2-16.3) years. Bronchiectasis was present in 24 (75%) children and air trapping was present in 29 (91%). Median (IQR) SIII of SBW was -138.4 (150.6) mg/mol. We found no association between SIII with either the MBW outcomes or CT scores (n = 23, association with bronchiectasis extent r = 0.10, P = 0.64). LCI and Scond were associated with bronchiectasis extent (n = 23, r = 0.57, P = 0.004; r = 0.60, P = 0.003, respectively). Acinar ventilation inhomogeneity measured by SBW was not associated with structural lung disease on CT. Double-tracer SBW added no benefit to indices measured by MBW.

One-year evolution and variability in multiple-breath washout indices in children and young adults with primary ciliary dyskinesia

ABSTRACTBackground and objective: Cross-sectional and longer-term studies have demonstrated abnormal yet stable multiple-breath inert gas washout (MBW) indices in patients with primary ciliary dyskinesia (PCD). This study aimed to assess the intermediate term evolution and the between-occasion variability of MBW indices in PCD over 1 year.Methods: Children and young adults with a confirmed diagnosis of PCD were included in this single-centre, prospective, observational, longitudinal study. Over 1 year, nitrogen (N2) MBW and spirometry were performed at three occasions during ordinary scheduled outpatient visits. Trends and variability in lung clearance index (LCI), moment ratios, normalized N2 concentration at six lung volume turnovers, and regional ventilation inhomogeneity indices of the conducting and intra-acinar airways (Scond*VT and Sacin*VT) were analysed using linear mixed models.Results: Forty-two patients, aged 6–29 years (median: 15.4), performed 116 N2 MBW test occasions and 96.6% were technically acceptable. A minimal, although significant, increase in LCI over 1 year (mean: 0.51 units, 95% CI: 0.12–0.91, p = 0.01) was found; while, all other N2 MBW indices and FEV1 remained unchanged. A moderate correlation was observed between LCI and FEV1 (r = −0.47, p = 0.0001). The limits of agreement between tests 1 year apart were for LCI: −1.96 to 2.98; Scond*VT: ± 0.039; Sacin*VT: −0.108 to 0.128.Conclusions: Children and young adults with PCD managed at a specialist centre showed slightly, but significant, increasing LCI and otherwise unchanged ventilation inhomogeneity indices and dynamic volumes over the intermediate term of 1 year. Estimates of the variability of N2 MBW indices may inform sample size calculations of future randomized controlled trials.

Modelling structural determinants of ventilation heterogeneity: A perturbative approach.

We have developed a computational model of gas mixing and ventilation in the human lung represented as a bifurcating network. We have simulated multiple-breath washout (MBW), a clinical test for measuring ventilation heterogeneity (VH) in patients with obstructive lung conditions. By applying airway constrictions inter-regionally, we have predicted the response of MBW indices to obstructions and found that they detect a narrow range of severe constrictions that reduce airway radius to 10%–30% of healthy values. These results help to explain the success of the MBW test to distinguish obstructive lung conditions from healthy controls. Further, we have used a perturbative approach to account for intra-regional airway heterogeneity that avoids modelling each airway individually. We have found, for random airway heterogeneity, that the variance in MBW indices is greater when indices are already elevated due to constrictions. By quantifying this effect, we have shown that variability in lung structure and mechanical properties alone can lead to clinically significant variability in MBW indices (specifically the Lung Clearance Index—LCI, and the gradient of phase-III slopes—Scond), but only in cases simulating obstructive lung conditions. This method is a computationally efficient way to probe the lung’s sensitivity to structural changes, and to quantify uncertainty in predictions due to random variations in lung mechanical and structural properties.

A simulation study of diffusion-convection interaction and its effect on multiple breath washout indices

Experimental studies of acinar ventilation heterogeneity (Sacin) derived from the multiple breath washout have shown the potential of Sacin to pick up structural change in lung disease. Recent Sacin data suggest that even when intra-acinar structure is unaltered, the combination of convection, diffusion and number of acini fed by patent terminal bronchioles can modify Sacin. We show here how Sacin is affected by structural features such as the secondary alveolar septa, intra-acinar ramification and number of ventilated acini. The simulations also predict relationships between respective alterations in Sacin and washout indices such as lung clearance index (LCI) and alveolar mixing efficiency (AME). This was verified experimentally, with highly significant correlations between Sacin and LCI (r = +0.85;p < 0.001) and between Sacin and AME (r = − 0.92; p < 0.001). We have shown how acinar ventilation heterogeneity can be affected by a reduction of number of ventilated acini, a change in overall alveolization or in intra-acinar alveolization pattern, via their impact on the balance between convection and diffusion at acinar level.

Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis.

The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.

A computational comparison of the multiple-breath washout and forced oscillation technique as markers of bronchoconstriction

Many types of lung disease lead to constriction of airways within the conducting zone, causing increases in airway resistance and ventilation heterogeneity (VH). The multiple-breath washout (MBW) and forced oscillation technique (FOT) are two clinical measures of small airway bronchoconstriction. Within this study computational modelling of the MBW and FOT was applied to the analysis of thousands of bronchoconstriction scenarios in the conducting zone of the lungs. The simulations show that MBW indices primarily respond to the severity of constriction, while FOT indices may be able to distinguish between constrictions at differing airway depths. Following this, we show the potential utility in the joint interpretation of indices from the two tests, providing motivations for future clinical investigations.

Modelling responses of the inert-gas washout and MRI to bronchoconstriction

Many lung diseases lead to an increase in ventilation heterogeneity (VH). Two clinical practices for the measurement of patient VH are in vivo imaging, and the inert gas multiple breath washout (MBW). In this study computational modelling was used to compare the responses of MBW indices LCI and scond and MRI measured global and local ventilation indices, σr and σlocal, to constriction of airways in the conducting zone of the lungs. The simulations show that scond, LCI and σr behave quite similarly to each other, all being sensitive to increases in the severity of constriction, while exhibiting little sensitivity to the depth at which constriction occurs. In contrast, the local MRI index σlocal shows strong sensitivity to depth of constriction, but lowered sensitivity to constriction severity. We finish with an analysis of the sensitivity of MRI indices to grid sizes, showing that results should be interpreted with reference to the image resolution. Overall we conclude that the application of both local and global VH measures may help to classify different types of bronchoconstriction.

Characterizing Lung Disease in Cystic Fibrosis with Magnetic Resonance Imaging and Airway Physiology.

Translational investigations in cystic fibrosis (CF) have a need for improved quantitative and longitudinal measures of disease status. To establish a non-invasive quantitative MRI technique to monitor lung health in patients with CF and correlate MR metrics with airway physiology as measured by multiple breath washout (MBW). Data were collected in 12 CF patients and 12 healthy controls. Regional (central and peripheral lung) measures of fractional lung water density (FLD: air to 100% fluid) were acquired both at FRC and TLC on a 1.5T MRI. The median FLD (mFLD) and the FRC-to-TLC mFLD ratio were calculated for each region at both lung volumes. Spirometry and MBW data were also acquired for each subject. Ventilation inhomogeneities were quantified by the lung clearance index (LCI) and by indices Scond* and Sacin* that assess inhomogeneities in the conducting (central) and acinar (peripheral) lung regions, respectively. MBW indices and mFLD at TLC (both regions) were significantly elevated in CF (p<0.01) compared to controls. The mFLD at TLC (central: R = 0.82) and the FRC-to-TLC mFLD ratio (peripheral: R = -0.77) were strongly correlated with Scond* and LCI. CF patients had high lung water content at TLC when compared to controls. This is likely due to the presence of retained airway secretions and airway wall edema (more water) and to limited expansions of air trapping areas (less air) in CF subjects. FRC-to-TLC ratios of mFLD strongly correlated with central ventilation inhomogeneities. These combined measures may provide a useful marker of both retained mucus and air trapping in CF lungs.

WS13.5 Structural correlation of multiple breath washout indices derived from alveolar slope analysis in adult cystic fibrosis

WS13.5 Structural correlation of multiple breath washout indices derived from alveolar slope analysis in adult cystic fibrosis K. Hurt1,2,3, D. Hansell3,4, A. Nair4, S. Sheard4, M. Hodson2,3, H. Kalsi2,3, D. Bilton2,3, O. Usmani2,3. 1Brighton and Sussex University Hospitals NHS Trust, Respiratory Medicine, Brighton, United Kingdom; 2Royal Brompton Hospital, Respiratory Medicine, London, United Kingdom; 3Imperial College, London, United Kingdom; 4Royal Brompton Hospital, Radiology, London, United Kingdom

WS13.6 Evidence of short-term acinar response following intravenous antibiotics therapy in adults with cystic fibrosis

WS13.5 Structural correlation of multiple breath washout indices derived from alveolar slope analysis in adult cystic fibrosis K. Hurt1,2,3, D. Hansell3,4, A. Nair4, S. Sheard4, M. Hodson2,3, H. Kalsi2,3, D. Bilton2,3, O. Usmani2,3. 1Brighton and Sussex University Hospitals NHS Trust, Respiratory Medicine, Brighton, United Kingdom; 2Royal Brompton Hospital, Respiratory Medicine, London, United Kingdom; 3Imperial College, London, United Kingdom; 4Royal Brompton Hospital, Radiology, London, United Kingdom

Repeatability and bronchodilator reversibility of lung function in young children

Knowledge of short- and longer-term repeatability of lung function in health and disease is essential to determine bronchodilator reversibility thresholds and to recognise if changes in lung function represent disease progression, therapeutic intervention or normal variability. Multiple-breath washout indices (lung clearance index, conductive ventilation inhomogeneity (Scond)) and specific airway resistance (sRaw) were measured in healthy children and stable wheezers. Measurements were performed at baseline and after 20 min without intervention to assess repeatability and determine bronchodilator reversibility thresholds. Bronchodilator reversibility was assessed by repeating baseline measurements 20 min after inhaled salbutamol. 28 healthy controls, mean±sd age 6.1±0.7 years and 62 wheezers 5.4±0.6 years were tested. Baseline variability in multiple-breath washout indices and sRaw was not significantly different between wheezers and healthy controls. Significant bronchodilator reversibility was only observed in wheezers for Scond (16%), but in both wheezers (37%) and healthy controls (20%) for sRaw. Some wheezers and healthy controls demonstrated increases in multiple-breath washout indices post-bronchodilator. Lung clearance index and sRaw demonstrate low baseline variability in healthy and diseased subjects. Neither multiple-breath washout indices nor sRaw are ideal for assessing bronchodilator reversibility in young children with stable wheeze. These findings will help to interpret the effect of therapeutic interventions in children with respiratory diseases.

Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung

RationaleSmall airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (Sacin) and conductive (Scond) lung zones,...

Ethnic Differences in Fraction of Exhaled Nitric Oxide and Lung Function in Healthy Young Children

Ethnic differences in lung function in school-aged children and adults are well recognized, but little is known about such differences in preschool children. We investigated whether differences exist in fraction of exhaled nitric oxide (Feno), multiple-breath washout (MBW) indices, specific airways resistance (sRaw), and spirometry indices between healthy preschool children of South Asian and white European origin. Feno, MBW indices (lung clearance index, functional residual capacity, conductive airways inhomogeneity, and acinar airways inhomogeneity), sRaw, and spirometry were measured in healthy South Asian and white children aged 4 to 6 years, and comparisons were made between the two groups. Statistical analyses were by multiple linear regression and t tests. Thirty-seven white (mean age 5.8 ± 0.7 years, 49% boys) and 31 South Asian children (mean age 5.4 ± 0.8 years, 52% boys) were recruited. Feno was, on average, 36% higher (P < .05) in South Asian children compared with white children. FVC and FEV(1) and fractions thereof (FEV(0.75) and FEV(0.5)) z-scores were significantly lower in South Asian compared with white children by 0.69 (P = .01), 0.76 (P = .004), 0.76 (P = .009), and 0.85 (P = .002) z-scores, respectively, but there were no significant differences in FEV(1)/FVC, FEF(25-75), sRaw, or MBW indices. Differences in Feno and forced expiratory lung volumes between South Asian and white children exist from a very young age. Ethnic differences should be taken into account when interpreting lung function results in preschool children for effective management of respiratory conditions.

Reproducibility of multiple breath washout indices in the unsedated preterm neonate

Multiple breath inert gas washout (MBW) is gaining popularity for measurements of resting lung volume and ventilation inhomogeneity. Test reproducibility is an important determinant of the clinical applicability of diagnostic tests. The between-test reproducibility of variables derived from MBW tests in newborn infants is unknown. We aimed to determine the within-test repeatability and short-term between-test reproducibility of MBW variables in unsedated preterm infants. We hypothesized that measurements obtained within a 3-day interval in clinically stable preterm infants would be reproducible and suitable for use as an objective clinical outcome measurement. In this cross-sectional observational study, clinically stable hospitalized preterm infants whose parents had given informed consent for MBW studies were tested twice within 72 hr during quiet, unsedated sleep. Functional residual capacity (FRC), lung clearance index (LCI), and the first and second to zeroeth moment ratios (M(1):M(0); M(2):M(0)) were computed from MBW traces obtained using a mainstream ultrasonic flowmeter and 4% sulphur hexafluoride (MBW(SF6)). Within-test repeatability and between-test reproducibility were determined. Within-test repeatability (expressed as a coefficient of variability (C(v))) for differences between two and four replicate measurements on the same test occasion, were 9.3% (FRC), 9.0% (LCI), 7.6% (M(1):M(0)), and 15.6% (M(2):M(0)), respectively. The within-test C(v)'s were not statistically different to the between-tests C(v)'s, which were 7.7% (FRC), 10.3% (LCI), 6.1% (M(1):M(0)), and 13.0% (M(2):M(0)), respectively. Among unsedated preterm infants, between-test reproducibility over a 3-day interval was similar to within-test repeatability. The wide limits of agreement may limit the application of these measures to detect a clinically significant change in condition in small preterm infants.