Lung Clearance Index Research Articles

Sulfur hexafluoride multiple breath washin and washout outcomes in infants are not interchangeable

Objective.Sulfur hexafluoride (SF6) multiple-breath washout (MBW) assesses ventilation inhomogeneity, as an early marker of obstructive respiratory diseases. Primary outcomes are customarily washout-derived, and it is unclear whether the preceding SF6-washin can provide similar estimates. We aimed to assess comparability of primary SF6-MBW outcomes between washin and washout phases of infant SF6-MBW data measured with the WBreath (ndd Medizintechnik AG, Zurich, Switzerland) and Spiroware (Eco Medics AG, Duernten, Switzerland) MBW-setups, respectively.Approach.We assessed mean relative differences in lung clearance index (LCI) and functional residual capacity (FRC) between the washin and washout of existing SF6-MBW data from healthy infants and infants with cystic fibrosis (CF). We assessed whether these differences exceeded the mean relative within-test between-trial differences of washout-derived outcomes, which can be attributed to natural variability. We also explored non-physiological factors using a pediatric lung simulator.Main results.LCI and FRC from washin and washout were not comparable, for both setups. The mean difference (SD) in LCI between washin and washout was 2.3(10.8)% for WBreath and -9.7(8.0)% for Spiroware, while in FRC it was -4.7(8.4)% for WBreath and -2.3(9.7)% for Spiroware. These differences exceeded the within-test between-trial differences in washout-derived outcomes. Outcomes from washin and washout were also not comparable in a pediatric lung simulator.Significance.Outcomes of the washin and washout were not comparable due to an interplay of physiological and non-physiological factors, and cannot be used interchangeably.

Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa after Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis.

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV1) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV1 of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = -1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire-Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis.

Non-local impact of distal airway constrictions on patterns of inhaled particle deposition.

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.

Body mass index trajectories from birth to early adulthood and lung function development.

Limited studies have investigated the influence of body mass index (BMI) trajectories on lung function covering the entire growth period. We conducted a prospective study utilizing data from the Swedish BAMSE birth cohort. Latent class mixture modelling was employed to examine the diversity in BMI z-scores from birth to 24 years of age. Participants with four or more BMI z-scores were included (n=3204, 78·4%). Pre-bronchodilator (BD) spirometry was tested at 8, 16, and 24 years, while post-BD spirometry, multiple-breath nitrogen washout (for lung clearance index, LCI), and urinary metabolomics data were assessed at 24 years. Six distinct BMI development groups were identified. Compared to the stable normal BMI group, the accelerated increasing BMI group exhibited reduced pre- and post-BD FEV1/FVC ratio z scores (β=-0·26, 95% CI=[-0·44, -0·08], and -0·22, [ -0·39, -0·05], respectively), along with elevated LCI (0·30, [0·22, 0·42]) at 24 years. The persistent high BMI group demonstrated lower FEV1, and FVC z scores growth between 16 and 24 years (-0.24, [-0.42, -0.05], and -0.27, [-0.45, -0.01], respectively), and elevated LCI (0·20, [0·03, 0·39]) at 24 years. However, those impairments were not observed in the accelerated resolving BMI group. Conversely, the persistent low BMI group displayed persistently decreased FEV1, and FVC from 8 to 24 years, as well as decreased lung function growth. Additionally, histidine-related metabolites were associated with pre- and post-BD FEV1 (hypergeometric FDR=0.008 and <0.001, respectively). Early interventions aiming for normal BMI during childhood may contribute to improved lung health later in life.

Dynamic 19F-MRI of pulmonary ventilation in lung transplant recipients with and without chronic lung allograft dysfunction

BackgroundBy the time chronic lung allograft dysfunction (CLAD), with its main phenotypes bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), is diagnosed by pulmonary function testing, irreversible damage to the lung allograft may already have occurred. Dynamic 19F-MRI of inhaled perfluoropropane may detect subtle changes in regional lung ventilation and provides a quantitative measure of regional lung function. We assessed feasibility of detecting regional ventilation dysfunction due to CLAD in lung transplant recipients. MethodsDynamic 19F-MRI was performed in ten lung transplant recipients, four without CLAD and six with CLAD (5 BOS, 1 RAS). Gas wash-in and washout dynamics were assessed and regional lung clearance index (RLCI) provided a quantitative metric of regional lung ventilation. ResultsBOS patients had substantially greater variation in regional ventilation compared with stable patients, with more regions of reduced ventilation, especially in the periphery. Tracer washout was homogeneous and rapid in stable patients but highly heterogeneous in CLAD. CLAD patients exhibited significant difference in RLCI between central and peripheral lung regions (p=0.0016) and a wider interquartile range of RLCI for wash-in compared with stable patients (no CLAD 4.1, BOS 10.5, p=0.036). FEV1 (% of baseline) negatively correlated with ventilation during wash-in, most strongly for the periphery (r=-0.844, p=0.0021). ConclusionsDynamic 19F-MRI identified quantifiable differences in regional ventilation in lung transplant recipients with and without CLAD and was well tolerated. Larger longitudinal studies using this approach will determine if early detection of changes in regional ventilation in lung transplant patients allows earlier CLAD detection.

ERS technical standard: Global Lung Function Initiative reference values for multiple breath washout indices.

Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC). Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated. Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age. Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC.

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

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. 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. 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 (β = 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. Increasing exposure to PM2.5 was associated with increased ventilation heterogeneity in the conductive region of the lungs 4 years after the event.

Association of Maternal Air Pollution Exposure and Infant Lung Function Is Modified by Genetic Propensity to Oxidative Stress.

The association between air pollution and poor respiratory health outcomes is well established. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. This study investigated maternal exposure to air pollution during pregnancy and oxidative stress (OS), inflammation, and infant lung function at 4 weeks of age. Data from the Barwon Infant Study were available for 314 infants. The exposure to NO2 and PM2.5 were estimated. Infant lung function (4 weeks) was measured by multiple-breath washout. Glycoprotein acetyls (GlycA) (36 weeks prenatal), cord blood, and OS biomarkers were measured in maternal urine (28 weeks). A genetic pathway score for OS (gPFSox) was calculated. Linear regression was used and potential modification by the OS genotype was tested. There was no relationship between maternal exposure to air pollution and infant lung function, or with GlycA or OS during pregnancy. We found an association in children with a genetic propensity to OS between NO2 and a lower functional residual capacity (FRC) (β = -5.3 mls, 95% CI (-9.3, -1.3), p = 0.01) and lung clearance index (LCI) score (β = 0.46 turnovers, (95% CI 0.10, 0.82), p = 0.01). High prenatal exposure to ambient NO2 is associated with a lower FRC and a higher LCI score in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.

Optimized algorithm for speed-of-sound-based infant sulfur hexafluoride multiple-breath washout measurements.

Major methodological issues with the existing algorithm (WBreath) used for the analysis of speed-of-sound-based infant sulfur hexafluoride (SF6) multiple-breath washout (MBW) measurements lead to implausible results and complicate the comparison between different age groups and centers. We developed OASIS-a novel algorithm to analyze speed-of-sound-based infant SF6 MBW measurements. This algorithm uses known context of the measurements to replace the dependence of WBreath on model input parameters. We validated the functional residual capacity (FRC) measurement accuracy of this new algorithm in vitro, and investigated its use in existing infant MBW data sets from different infant cohorts from Switzerland and South Africa. In vitro, OASIS managed to outperform WBreath at FRC measurement accuracy, lowering mean (SD) absolute error from 5.1 (3.2) % to 2.1 (1.6) % across volumes relevant for the infant age range, in variable temperature, respiratory rate, tidal volume and ventilation inhomogeneity conditions. We showed that changes in the input parameters to WBreath had a major impact on MBW results, a methodological drawback which does not exist in the new algorithm. OASIS produced more plausible results than WBreath in longitudinal tracking of lung clearance index (LCI), provided improved measurement stability in LCI over time, and improved comparability between centers. This new algorithm represents a meaningful advance in obtaining results from a legacy system of lung function measurement by allowing a single method to analyze measurements from different age groups and centers.

The predictive role of lung clearance index on FEV1 decline in cystic fibrosis.

The lung clearance index (LCI) is a sensitive lung function index that is used to detect early lung disease changes in children with cystic fibrosis (CF). This study aimed to define the predictive role of baseline LCI, along with other potential factors on the change in forced expiratory volume in one second (FEV1) during one-year follow-up in CF patients who had a percent predicted (pp) FEV1≥80. LCI was concurrently performed on 57 CF patients who had ppFEV1 ≥80 at month zero. The ppFEV1 decline was evaluated prospectively during the one year follow up. The primary outcome of ppFEV1 decline in the study group in one year was dichotomized according to the median value for the decline in ppFEV1, which was 3.7. The LCI value predicting ppFEV1 decline at the end of one year was calculated with receiver operating characteristic curve analysis. Regression analysis was performed. Furthermore, a decision tree was constructed using classification and regression tree methods to better define the potential effect of confounders on the ppFEV1 decline. The LCI value for predicting ppFEV1 decline >3.7% at the end of one year was 8.2 (area under the curve: 0.80) Multivariable regression analysis showed that the absence of the F508del mutation in at least one allele, LCI >8.2 and initial FEV1 z-score were predictors of a ppFEV1 decline >3.7 (p<0.001). Factors altering ppFEV1 decline>3.7% at the end of one-year evaluated by decision trees were as follows: initial FEV1 z-score, type of CFTR mutation, LCI value and initial weight-for-age z-score. LCI is sensitive for predicting ppFEV1 decline in patients with ppFEV1 ≥80 along with the initial FEV1-z-score and type of CFTR mutation.

Telemedicine and home spirometry in cystic fibrosis: A prospective multicenter study.

Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care. Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires. A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV1%, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine. Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care.

Impact of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles.

We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6-11 years with CF and one or two F508del alleles. This prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI. A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (-1.0 (-2.0- -0.1); p<0.01) and F/F children (-0.8 (-1.9- -0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (-4.0 (-9.0-0.0); p<0.01) and F/F children (-3.5 (-7.3- -0.8); p<0.001). ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del allele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening – A nationwide observational study

BackgroundNon-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. MethodsLung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 – 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. ResultsLCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. ConclusionsThe LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.

P168 Clinical utility and application of lung clearance index (LCI) for cystic fibrosis screen positive, inconclusive diagnosis (CFSPID) and adults with an unclear CF diagnosis

P168 Clinical utility and application of lung clearance index (LCI) for cystic fibrosis screen positive, inconclusive diagnosis (CFSPID) and adults with an unclear CF diagnosis

P167 The relationship of lung clearance index with radiological and microbiological findings and spirometric parameters in children with cystic fibrosis with normal FEV1 values

P167 The relationship of lung clearance index with radiological and microbiological findings and spirometric parameters in children with cystic fibrosis with normal FEV1 values

P165 Lung clearance index in adult patients with atypical cystic fibrosis and normal FEV1

P165 Lung clearance index in adult patients with atypical cystic fibrosis and normal FEV1

P169 Lung clearance index as an alternative respiratory outcome in elexacaftor/tezacaftor/ivacaftor treated patients without clinically important improvement in forced expiratory volume in one second

P169 Lung clearance index as an alternative respiratory outcome in elexacaftor/tezacaftor/ivacaftor treated patients without clinically important improvement in forced expiratory volume in one second

P166 Utility of lung clearance index (LCI2.5) as an outcome measure in cystic fibrosis clinical trials – perspectives of people with cystic fibrosis and LCI2.5 operators

P166 Utility of lung clearance index (LCI2.5) as an outcome measure in cystic fibrosis clinical trials – perspectives of people with cystic fibrosis and LCI2.5 operators

Lung Clearance Index as a Screening Parameter of Pulmonary Impairment in Patients under Immune Checkpoint Therapy: A Pilot Study.

Background: Immune checkpoint blockade (ICB) has presented a breakthrough in the treatment of malignant tumors and increased the overall survival of patients with various tumor entities. ICB may also cause immune-related adverse events, such as pneumonitis or interstitial lung disease. The lung clearance index (LCI) is a multiple-breath washout technique offering information on lung pathology in addition to conventional spirometry. It measures the degree of pulmonary ventilation inhomogeneity and allows early detection of pulmonary damage, especially that to peripheral airways. Methods: This cross-sectional study compared the lung function of patients with melanoma or metastatic cutaneous squamous cell carcinoma who received programmed cell death 1 (PD-1) and cytotoxic T-Lymphocyte-associated Protein 4 (CTLA-4) antibodies, alone or in combination, to age- and sex-matched controls. Lung function was assessed using spirometry, according to American Thoracic Society and European Respiratory Society standards, the LCI, and a diffusion capacity of carbon monoxide (DLCO) measurement. Results: Sixty-one screened patients and thirty-eight screened controls led to nineteen successfully included pairs. The LCI in the ICB-treated patients was 8.41 ± 1.15 (mean ± SD), which was 0.32 higher compared to 8.07 ± 1.17 in the control group, but the difference was not significant (p = 0.452). The patients receiving their ICB therapy for under five months showed a significantly lower LCI (7.98 ± 0.77) compared to the ICB patients undergoing therapy for over five months (9.63 ± 1.22) at the point of testing (p = 0.014). Spirometric analysis revealed that the forced expiratory volume between 25 and 75% of the forced vital capacity (FEF25-75%) in the ICB-treated patients was significantly reduced (p = 0.047) compared to the control group. DLCO (%predicted and adjusted for hemoglobin) was 94.4 ± 19.7 in the ICB patients and 93.4 ± 21.7 in the control group (p = 0.734). Conclusions: The patients undergoing ICB therapy showed slightly impaired lung function compared to the controls. Longer periods of ICB treatment led to deterioration of the LCI, which may be a sign of a subclinical inflammatory process. The LCI is feasible and may be easily integrated into the clinical daily routine and could contribute to early detection of pulmonary (auto-)inflammation.

Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.

Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.