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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., Competing Interests: Conflict of interest: N. Sonneveld has nothing to disclose. Conflict of interest: J.H. Rayment has nothing to disclose. Conflict of interest: J. Usemann has nothing to disclose. Conflict of interest: K.G. Nielsen has nothing to disclose. Conflict of interest: P.D. Robinson has nothing to disclose., (Copyright ©The authors 2023.)

Sensor errors resulting in elevated values of N 2 concentration [N 2 ] in commercial multiple-breath washout (MBW) devices have been shown to prolong the washout and result in erroneously high functional residual capacity (FRC) and lung clearance index (LCI) values. The errors also affect the indices of conductive and acinar ventilatory heterogeneity ( S cond and S acin ) against lung turnover (TO) from a TO range starting at 1.5 and ending at an upper turnover (TO S cond was calculated using regression of normalized phase III slope (Sn III ) against lung turnover (TO) from a TO range starting at 1.5 and ending at an upper turnover (TO upper ) between 4 and 8 (default 6) over a range of simulated values. The principal effect of the sensor error was that as the MBW proceeded the phase III slope of successive breaths was normalized by an increasingly overestimated [N 2 ], resulting in Sn III values that fell precipitously at high TO, greatly reducing S cond . Reanalysis of previously published data and of simulated data showed a large proportional bias in S cond , whereas S acin was only minimally affected. In adult subject data, reducing TO upper below 5.5 was associated with a large drop of up to ∼60% in S cond calculated from data corrected for sensor error. Raising the upper TO limit elevated S cond by ∼20% but with a large concomitant increase in variability. In contrast to S cond , S acin was relatively unaffected by changes in TO upper with changes of <3%. This work serves to emphasize that the upper limit of TO of 6 represents an appropriate upper limit for the calculation of S cond . NEW & NOTEWORTHY Sensor errors that elevated values of N 2 concentration in commercial multiple-breath washout (MBW) devices resulted in errors in calculated parameters including S cond and S acin . We examined the mechanism of the change in values produced by these errors and explored the appropriateness of the calculation of S cond and S acin . This work serves to emphasize that the current algorithm in use is appropriate for the calculation of S cond and S acin .

Cystic fibrosis (CF) lung disease is characterized by increased ventilation inhomogeneity (VI), as measured by multiple-breath washout (MBW). Lung clearance index (LCI) is the most reported VI outcome. This study aimed to evaluate historically published reference equations for sulfur hexafluoride (SF 6 ) MBW outcomes, to data collected using updated commercial SF 6 MBW equipment, and to produce device-specific equations if necessary. SF 6 MBW was performed in 327 healthy children aged 0.1-18.4 yr [151 (46%) girls], 191 (58.4%) <3 yr. z-Scores were calculated from published reference equations (FRC and LCI) and multivariate linear regression was performed to produce device-specific reference equations. Due to increasing residual standard deviations with increasing LCI values, investigation of methods for improvement were investigated, based on the relationship between VI and dead space ventilation (VD/VT; dead space volume/tidal volume) in a cohort of 59 healthy children, 26 children with CF ( n = 138 test occasions), and 49 adults with lung disease. Historical SF 6 MBW reference equations were unsuitable for EXHALYZER D data. In contrast to LCI and log 10 (LCI), 1/LCI (ventilation distribution efficiency; VDE) was linearly related to VD/VT, with z-scores linearly related to its absolute values. Reference equations were reported for VDE and log 10 (FRC). Significant predictors for VDE and log 10 (FRC), respectively, were log 10 (age) and sex, and log 10 (height), sex, and posture. VDE is potentially a better index of VI than LCI, particularly in more advanced CF lung disease and also for longitudinal monitoring. Further confirmatory clinical studies, particularly longitudinal imaging studies of structural or ventilatory changes, are warranted. NEW & NOTEWORTHY Lung clearance index (LCI) is the most used outcome from the multiple-breath washout test. As known for decades, the LCI is not linearly related to dead space ventilation, giving difficulties interpreting changes over time and in clinical trials. We present a new and improved outcome based on LCI, the ventilation distribution efficiency (VDE), which solves this problem by being linearly related to dead space ventilation. A pediatric age range reference equation for VDE is presented.

Recent studies indicate limited utility of nitrogen multiple-breath washout (N 2 MBW) in infancy and advocate for using sulfur hexafluoride (SF 6 ) MBW in this age-group. Modern N 2 MBW systems, such as EXHALYZER D (ECO MEDICS AG, Duernten, Switzerland), use O 2 and CO 2 sensors to calculate N 2 concentrations (in principle, N 2 % = 100 - CO 2 % - O 2 %). High O 2 and CO 2 concentrations have now been shown to significantly suppress signal output from the other sensor, raising apparent N 2 concentrations. We examined whether improved EXHALYZER D N 2 signal, accomplished after thorough examination of this CO 2 and O 2 interaction on gas sensors and its correction, leads to better agreement between N 2 MBW and SF 6 MBW in healthy infants and toddlers. Within the same session, 52 healthy children aged 1-36 mo [mean = 1.30 (SD = 0.72) yr] completed SF 6 MBW and N 2 MBW recordings (EXHALYZER D, SPIROWARE version 3.2.1) during supine quiet sleep. SF 6 and N 2 SPIROWARE files were reanalyzed offline with in-house software using identical algorithms as in SPIROWARE with or without application of the new correction factors for N 2 MBW provided by ECO MEDICS AG. Applying the improved N 2 signal significantly reduced mean [95% confidence interval (CI)] differences between N 2 MBW and SF 6 MBW recorded functional residual capacity (FRC) and lung clearance index (LCI): for FRC, from 26.1 (21.0, 31.2) mL, P < 0.0001, to 1.18 (-2.3, 4.5) mL, P = 0.5, and for LCI, from 1.86 (1.68, 2.02), P < 0.001, to 0.44 (0.33, 0.55), P < 0.001. Correction of N 2 signal for CO 2 and O 2 interactions on gas sensors resulted in markedly closer agreement between N 2 MBW and SF 6 MBW outcomes in healthy infants and toddlers. NEW & NOTEWORTHY Modern nitrogen multiple-breath washout (N 2 MBW) systems such as EXHALYZER D use O 2 and CO 2 sensors to calculate N 2 concentrations. New corrections for interactions between high O 2 and CO 2 concentrations on the gas sensors now provide accurate N 2 signals. The correct N 2 signal led to much improved agreement between N 2 MBW and sulfur hexafluoride (SF 6 ) MBW functional residual capacity (FRC) and lung clearance index (LCI) in 52 sleeping healthy infants and toddlers, suggesting a role for N 2 MBW in this age-group.

Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Uncontrolled severe asthma in children is burdensome and challenging to manage. This study aims to describe outcomes in children with uncontrolled severe asthma managed in a nurse-led severe asthma clinic (SAC)., Methods: This retrospective analysis uses data collected from children referred by a paediatric respiratory specialist to a nurse-led SAC for uncontrolled severe asthma between 2014 and 2019. The pre-clinical assessments included a home visit to assess modifiable factors that could be addressed to improve control. A comprehensive lung function analysis was conducted at each visit. Interventions were personalised and included biologic agents. Statistical analysis was performed using nonparametric, two-tailed Mann-Whitney U-test, the parametric Student's t-test, or analysis of variance (ANOVA) as appropriate., Results: Twenty-three children with a median age of 12 years were seen once, and 16 were followed up. Compared to a non-asthmatic (NA) and asthmatic (A) age-matched cohort, children with severe asthma (SA) had a lower FEV1, and FVC% predicted before and after bronchodilator inhalation, and a higher mean Lung Clearance Index [LCI] (10.5 [SA] versus 7.3 [NA] versus 7.6 [A], p = 0.003). Almost 80% of children with SA had an abnormal LCI, and 48% had a reduced FEV1% at the first SAC visit. Asthma control and FEV1% predicted significantly improved at a follow-up visit, while LCI remained abnormal in the majority of children (83%)., Conclusion: Over time, many children with severe asthma showed improved clinical outcomes and lung function while lung ventilation inhomogeneities persisted. Future appropriately controlled studies are required to determine if a nurse-led multidisciplinary SAC is associated with better outcomes.

Background: Data on long term variability of Lung Clearance Index (LCI) in Cystic Fibrosis (CF) is urgently needed to guide test result interpretation. Our aim was to evaluate LCI variability in clinically stable CF lung disease in school age children., Methods: Paediatric patients, aged 6 to 17years, attending the outpatient CF clinic performed Multiple Breath Nitrogen Washout (Exhalyzer® D) and spirometry every third month over a period of one year. Clinical stability was assessed by the Cystic Fibrosis Clinical Score (CFCS) at each visit., Results: Twentyfive children were recruited: baseline median (range) FEV 1 % pred. 91 (55-122)%, LCI 9.1 (6.4-18.6), CFCS 15 (12-23). A total of 107 visits were included in the study, of which 93% were defined as clinically stable. In clinically stable visits, within-subject variability of LCI and FEV 1 % pred. were 10% and 16%, respectively. The upper limit of normal (ULN, 95% percentile) of LCI variability during clinical stability was 17%., Conclusions: LCI within-subject variability was low and comparable to FEV 1 % pred. which strengthen the use of LCI to monitor lung disease progression in CF patients. An increase in LCI >17% compared to previous LCI-measurement in clinically stable CF patients may therefore indicate early lung disease progression., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O 2 ) and sulfur hexafluoride (SF 6 )] but detailed comparisons are lacking. N 2 - and SF 6 -based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O 2 and 4% SF 6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O 2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO 2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N 2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF 6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N 2 vs. SF 6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF 6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O 2 and movement of O 2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF 6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work.

Purpose: The purpose of this study was to compare (i) the exercise capacity and (ii) lung function prior to and immediately post cardiopulmonary exercise tests (CPET) of children who underwent early life lung resection for Congenital Pulmonary Airway Malformations (CPAM) to healthy control children., Method: Eight children with CPAM (four males, age 9.6 ± 1.8 years) and eight control children without respiratory disease (three males, age 9.4 ± 1.4 years) performed a CPET on a cycle ergometer, during which maximal oxygen consumption (V̇O 2max ) and heart rate were measured. Prior to and immediately post CPET, lung function measures including Nitrogen Multiple Breath Washout (MBW) and spirometry were performed., Results: There were no significant between group differences in pre CPET lung function (P > 0.05) or maximal exercise capacity (V̇O 2max CPAM: 39.4 mL . kg -1. min -1 , Control: 40.5 mL . kg -1. min -1 ). Post CPET, FEV 1 was significantly lower in the CPAM group, with two participants diagnosed subsequently with exercise induced bronchospasm based on post-CPET spirometry and follow-up clinical investigations., Conclusion: Early life lung resection for CPAM does not appear to have negative implications for exercise capacity later in childhood. Clinicians should be aware that dyspnoea following exercise may be due to asthma rather than residual effects of CPAM in these children., (© 2017 Wiley Periodicals, Inc.)

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N 2 )-based MBW is of concern given the detrimental effect of exposure to pure O 2 on infant breathing pattern. We propose novel methodology using commercially available N 2 MBW equipment to facilitate 4% sulfur hexafluoride (SF 6 ) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO 2 , O 2 , and sidestream molar mass sensor signals were used to accurately calculate SF 6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use., (Copyright © 2016 the American Physiological Society.)

Suboptimal asthma control is common despite modern asthma therapy. The degree of peripheral airway involvement remains unclear and poor medication delivery to these regions might be a contributing reason for this failure in obtaining adequate symptom control. A cohort of 196 adults (median (range) age 44 (18-61) years, 109 females, 54 ex-smokers, six current smokers) with physician-diagnosed asthma were recruited from primary care. Subjects were characterized clinically by interviews, questionnaires, skin prick tests (SPT) and blood eosinophil counts. Lung function was assessed by spirometry, impulse oscillometry (IOS) and nitrogen multiple breath washout (N2 MBW). IOS assessed peripheral airway resistance (FDR, frequency dependence of resistance). N2 MBW assessed global ventilation inhomogeneity (LCI, lung clearance index), specific indices of peripheral airway function (Scond × VT and Sacin × VT; VT, tidal volume), and inter-regional inhomogeneity (specific ventilation ratio). Never-smoking healthy cohorts of 158 and 400 adult subjects provided local reference values for IOS and N2 MBW variables, respectively. Peripheral airway dysfunction was detected in 31% (FDR or specific ventilation ratio) to 47% (Scond x VT) of subjects. Risk factors for peripheral airway dysfunction were identified. Among subjects with low FEV1 and either positive smoking history and/or blood eosinophilia (>4.0%), 63% had abnormality across all peripheral airway outcomes, whilst only one subject was completely normal. Abnormal peripheral airway function was present in a large proportion of adult asthmatics at baseline. Reduced FEV1, a positive smoking history, and/or blood eosinophilia identified "a small airway asthma subtype" that might benefit from peripheral airway targeted therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis., (Copyright © 2014 the American Physiological Society.)