Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or ...symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV
) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV
decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV
≥90% predicted) and 'mild lung disease' (FEV
70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.
Optimal characterisation of early structural abnormalities has been highlighted as critical to future efforts to detect and prevent cystic fibrosis (CF) lung disease progression 1. Computed ...tomography (CT) is currently the gold standard, detecting structural disease at an earlier stage than radiography or lung function testing, with predictive value for subsequent progression and later forced expiratory volume in 1 s (FEV
1
) decline 1. Compared to other emerging radiological modalities for early disease detection, such as magnetic resonance imaging (MRI), CT is more widely accessible and MRI at present is not able to directly quantify the extent of bronchiectasis due to its limitations in spatial resolution. Current US CF Foundation clinical guidelines state that CT should be “considered every 2–3 years, using the lowest possible radiation dose” 2. Early lung disease is identified on CT by air trapping, increase in airway wall thickness and airway diameter, and potentially irreversible bronchiectasis 3. Spirometer-directed CT has standardised lung volume acquisition and outlined the importance of both inspiratory and expiratory image acquisition 4. Consensus recommendations for “low dose” CT scanning were published in 2016 5, but radiation exposure remains a concern, given the six-fold increase in CT use and ongoing increase in cumulative radiation exposure for CF patients 6. Imaging requires optimal structural information at the lowest possible radiation dose 5. Given the increased vulnerability of children to ionising radiation, “low dose” CT protocols have already been incorporated in paediatric clinical trials using CT-based primary outcome measures 7, and use of ultra-low dose (ULD) CT has emerged in adult CF research and in isolated paediatric patients 6. However, formal validation of the effects on quantitative measures of structural disease has not been performed. Low dose (LD) CT shows limitations compared to standard dose CT because of known drifts in CT lung density dependent on dose 8. We hypothesised that ULD implementation would not detrimentally affect structural disease detection in early CF lung disease, and specifically targeted an age range to explore this where volume variation during spirometry-directed CT could be minimised between imaging modalities. Thus, the primary aims in this study were to 1) implement spirometer-directed novel ULD CT in school-aged children with CF, and 2) validate its outcomes against same-session LD CT using visual as well as fully automated quantitative CT analysis for structural airway disease.
Early cystic fibrosis lung disease requires urgent sensitive outcome measures. Ultra-low dose CT provides comparable quantitative structural insight into bronchiectasis compared to conventional low dose CT, but higher rates of air trapping.
https://bit.ly/3Wi8MLr
Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF
) and nitrogen (N
)) and different devices, all of which give discrepant results. This study aimed to ...confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used.
Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N
) and Innocor (SF
)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout.
Breath number was higher with N
washout than SF
in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS.
N
MBW results were higher than SF
MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N
and SF
MBW results are inherently different and should be considered as independent measurements.
Thank you for the opportunity to respond to the correspondence by J.G. Nielsen from Innovision about our recent paper 1. We would like to respond with a few points to address any concerns that may ...have arisen from his comments amongst colleagues at cystic fibrosis centres using the Exhalyzer D (Eco Medics, Dürnten, Switzerland).
Addressing concerns with use of the Exhalyzer D multiple breath washout device
http://bit.ly/2ug0fAi
This study examined the effects of different pressure threshold inspiratory loads on lactate clearance and plasma acid-base balance during recovery from maximal exercise.
Eight moderately trained ...males (V˙O(2peak) = 4.29 ± 0.46 L·min⁻¹) performed, on different days, four maximal incremental cycling tests (power started at 0 W and increased by 20 W·min⁻¹) of identical duration (exercise time during the first trial was 16.32 ± 1.12 min). During 20-min recovery, subjects either rested passively or breathed through a constant pressure threshold inspiratory load of 10 (ITL10), 15 (ITL15), or 20 (ITL20) cm H2O. Plasma lactate concentration (La⁻) was measured, and acid-base balance was quantified using the physicochemical approach, which describes the dependency of H⁺ on the three independent variables: strong ion difference (Na⁺ + K⁺ - Cl⁻ + La⁻), the total concentration of weak acids, and the partial pressure of carbon dioxide.
Peak exercise responses were not significantly different between trials. During recovery, the area under the plasma La curve was not different between trials (pooled mean = 261 ± 60 mEq) and the La measured at the end of the 20-min recovery was also similar (passive recovery = 9.2 ± 3.1 mEq·L⁻¹, ITL10 = 9.3 ± 3.1 mEq·L⁻¹, ITL15 = 8.7 ± 2.8 mEq·L⁻¹, ITL20 = 8.7 ± 3.2 mEq·L⁻¹). Similarly, changes in other strong ions contributing to strong ion difference and total concentration of weak acids, partial pressure of carbon dioxide, and, therefore, H⁺ were not different between trials.
These data suggest that, in individuals of moderate endurance training status, inspiratory loading at the intensities used in the present study does not accelerate lactate clearance or modify plasma acid-base balance during recovery from maximal exercise.
•In early lung disease, multiple breath washout and CT are complementary tools.•MBW and CT detect more abnormality than oscillometry, CPET and spirometry.•Sensitivity of MBW to detect abnormality can ...be increased by Scond and MBW-assessed trapped gas.
Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children.
50 CF subjects (mean±SD 11.2 ± 3.5y, range 5–18y) with early lung disease (FEV1≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT).
CT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82 %, MBWTG RV 78 %, LCI 74 %, MBWTG IC 68 % and Sacin 51 %. CPET VO2peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r = 0.55–0.64, p < 0.001) and AT (r = 0.73–0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %.
Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
