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Practicability of nitrogen multiple-breath washout measurements in a pediatric cystic fibrosis outpatient setting
Abstract
BACKGROUND: Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N2 ) MBW setup to assess success rate, duration, and variability of LCI within a 20 min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease.
METHODS: One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naïve to MBW. Within 20 min, each child was trained, N2 MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children.
RESULTS: At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection.
CONCLUSIONS: Using available N2 MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease. Longer timeframes would be required for triplicate N2 MBW tests in inexperienced children.
... Early CF lung disease usually arises peripherally, whereas FEV1 allows us to detect changes in the large airways. Therefore, LCI is a more sensitive marker than spirometry in detecting early signs of lung disease [10,11]. It is repeatable, and its results correlate with high-resolution computed tomography outcomes [12]. ...
... The baseline characteristics of the study cohort fulfilling the inclusion criteria are presented in Table 1. The average length of antibiotic therapy was 13 days ± 1 day [10][11][12][13][14][15][16][17]. Amikacin and ceftazidime were the most commonly used antibiotics for treatment (65%), colistin and ceftazidime were used in 5%, and other therapy in 30% of patients. ...
... It showed that the coefficient of repeatability between tests occasions performed 24 h apart was 0.96 in CF children compared to 0.62 in controls. This observation also shows that a change in LCI of at least one unit is clinically meaningful in children with CF [10]. ...
1) Background: Pulmonary exacerbation (PEx) is one of the main factors affecting the quality of life and life expectancy in patients with cystic fibrosis (CF). Our study aimed to evaluate the change in selected pulmonary function parameters, including lung clearance index (LCI), in patients with CF diagnosed with PEx. (2) Methods: We enrolled 40 children with CF aged 6-17. They performed spirometry and multiple breath nitrogen washout (MBNW) tests during a stable condition period at the beginning and the end of intravenous antibiotic treatment. (3) Results: LCI increased by 65% and FEV1 decreased by ≥10% in 40% of patients with CF during PEx. An absolute change in LCI between a stable condition period and PEx was 1.05 (±1.92) units, which corresponds to a relative change of 11.48% (±18.61) of the baseline. The relative decrease in FEV1 was −9.22% (±12.00) and the z-score was −0.67 (±1.13). After the PEx treatment, FEV1 increased by 11.05% (±9.04) on average, whereas LCI decreased by 1.21 ± 1.59 units on average, which represented 9.42% ± 11.40 compared to the value at the beginning of PEx. (4) Conclusions: The change in LCI captures a higher proportion of events with functional impairment than FEV1 in school-age children with CF.
... L'ICP est corrélé avec plusieurs indicateurs de la sévérité de l'atteinte pulmonaire, comme les variables dérivées de la spirométrie [49], le score clinique [78,85], certains marqueurs inflammatoires [86][87][88], la charge bactérienne [86,89], et le statut de colonisation par Pseudomonas aeruginosa [76,88]. Surtout, cet indice est bien mieux corrélé que les paramètres spirométriques avec les scores obtenus en imagerie par la résonance magnétique [77,90] ou la tomodensitométrie thoracique (CT-scan), qui est l'examen de référence pour évaluer la présence et l'étendue de dommages pulmonaires structurels dans la MV. ...
... Plus récemment, chez des enfants stables suivis chaque trimestre pendant 1 an, c'est plutôt un seuil de 25 % d'augmentation de l'ICP qui a semblé traduire une évolution défavorable [118,119]. Parce que la variabilité de l'ICP augmente proportionnellement avec sa valeur absolue, un tel seuil est en tout cas clairement plus crédible que la simple augmentation d'une unité de l'ICP parfois évoquée, sur base du coefficient de répétabilité de l'indice chez les sujets en bonne santé [66,76,78,95,120]. La reproductibilité des mesures est particulièrement importante si l'ICP doit être utilisé comme outil d'évaluation d'un traitement. ...
... Dans un contexte clinique, la faisabilité a également été testée en imposant une contrainte de temps de 20 minutes à des enfants naïfs au test RCM. Le taux de succès chute alors à 60 % chez les enfants âgés de 3 à 6 ans et 41 % chez les enfants de 4-16 ans [76,124]. Les principales raisons ayant contrarié l'obtention d'au moins deux mesures valides au cours du temps imparti étaient liées à la présence d'une fuite, d'un pattern respiratoire irrégulier ou à l'arrêt prématuré du test par l'enfant. ...
Introduction:
Small airways' involvement in cystic fibrosis (CF) pulmonary disease is a very early event, which can progress sub-clinically and insidiously since it is poorly reflected by commonly used lung function tests.
State of art:
Sensitive and discriminative tools are available to investigate small airways function. However their complexity and/or invasiveness has confined their use to research purposes and to some specialized research teams. By contrast, the multiple breath washout (MBW) test is more affordable and non-invasive. Lung clearance index (LCI), which is the most used derived parameter, is reproducible and much more sensitive than spirometry in detecting small airways disease. However, MBW is operator dependent.
Perspectives:
The recent commercialization of devices assessing LCI launches MBW as a potential tool in routine clinical care, although its use currently remains mostly dedicated to research purposes. However, important differences in LCI between various equipment settings raise a number of theoretical questions. Specific algorithms should be refined and more transparent. Standardization of MBW is still an ongoing process. Whether other MBW derived indices can prove superior over LCI deserves further study.
Conclusions:
In CF, LCI is now a well-established outcome in research settings to detect early lung function abnormalities and new treatment effects, especially in patients with mild lung disease. In these patients, LCI seems an attractive tool for clinicians too. Yet, further investigation is needed to define clinically significant changes in LCI and to which extent this index can be useful in guiding clinical decisions remains to be studied.
... Investigators report differing findings for the inter-test reproducibility of the LCI due to variability in protocol designs, study population and MBW methodology [5][6][7][8][9][10][11][12][13][14]. Most notably, time intervals between repeated tests range from hours to years, and none report reproducibility for time intervals typically used to clinically track patients with cystic fibrosis (e.g. ...
... quarterly) [6,11,15]. Comparison between studies is further limited by the various methodologies that define reproducibility; coefficient of variation (%CV) [5,7,8], the intra-class correlation coefficient (ICC) [6], the limits of agreement from Bland-Altman plots [5,[9][10][11] or the coefficient of reproducibility [12,13]. Reproducibility has most commonly been reported as Bland-Altman limits of agreement or coefficient of repeatability. ...
... Reproducibility has most commonly been reported as Bland-Altman limits of agreement or coefficient of repeatability. Both of these methods assume that the measurement variability is independent of its magnitude, and analyses have only been tested in health or for a narrow range of LCI values in participants with cystic fibrosis [12,15]. If this assumption is not valid across the spectrum of values observed in clinical practice, the use of the limits of agreement or coefficient of repeatability may introduce bias in the interpretation of clinically relevant between-visit changes in the LCI. ...
The lung clearance index (LCI) has strong intra-test repeatability; however, the inter-test reproducibility of the LCI is poorly defined.
The aim of the present study was to define a physiologically meaningful change in LCI in preschool children, which discriminates changes associated with disease progression from biological variability.
Repeated LCI measurements from a longitudinal cohort study of children with cystic fibrosis and age-matched controls were collected to define the inter-visit reproducibility of the LCI. Absolute change, the coefficient of variation, Bland–Altman limits of agreement, the coefficient of repeatability, intra-class correlation coefficient, and percentage changes were calculated.
LCI measurements (n=505) from 71 healthy and 77 cystic fibrosis participants (aged 2.6–6 years) were analysed. LCI variability was proportional to its magnitude, such that reproducibility defined by absolute changes is biased. A physiologically relevant change for quarterly LCI measurements in health was defined as exceeding ±15%. In clinically stable cystic fibrosis participants, the threshold was higher (±25%); however, for measurements made 24 h apart, the threshold was similar to that observed in health (±17%).
A percentage change in LCI greater than ±15% in preschool children can be considered physiologically relevant and greater than the biological variability of the test.
... 21 There are few studies looking into long-term LCI variability in CF children and the existing results are discordant. In children aged 4-16 years, Singer et al. 38 and Stanojevic 7 and colleagues independently postulated that a change in LCI of 1 unit is relevant for diagnosing exacerbation. In the present study, we have shown that an increase in LCI of 1.6 units is a significant indicator of PE. ...
... This is more than previously reported (1.0-0.87 unit). 7,21,38,39 We used different LCI values than in the papers that had been published before. We recalculated the LCI results after the reports that showed erroneous calculations provided by the Exhalyzer software in the past several years that overestimated LCI by approximately 15% in children with CF. 28,29 Therefore our results cannot be directly compared with the results that had been published before. ...
Background:
Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the FEV1 decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE.
Methods:
We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS).
Results:
Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for LCI, Sacin , R5Hz, R5-20Hz, X10Hz, AX and Fres. The predictive values of Fres and X10Hz in IOS (AUCROC 0.71 both parameters) were higher than those of LCI (AUCROC 0.67). There was no difference in the predictive values (AUCROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV1 z-score ≥ -1.64 and AUC 0.69 for LCI vs 0.69 for both ΔX10Hz z-score and Δ Fres z-score).
Conclusions:
Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with pulmonary exacerbation. LCI has a similar predictive value to IOS in children with CF independently of their FEV1 value. This article is protected by copyright. All rights reserved.
... Validation of MBW equipment is recommended, and the in vitro precision of measured functional residual capacity (FRC) for several devices using a double chamber plastic lung model is within 5% across a range of lung volumes and respiratory frequencies [11][12][13][14]. The availability of commercial devices has helped facilitate the implementation of MBW into multicentre international research studies [15,16], and its transition into routine clinical practice [17]. In this review we describe the MBW test, its applications and challenges, and directions for future research. ...
... nitrogen) are washed-out by breathing 100% oxygen (figure 1). One of the advantages of MBW is that it can be performed during tidal (normal) breathing, which makes it ideally suited for infants and young children, as well as some adults, who have trouble performing the forced manoeuvres required for standard pulmonary function tests [17,18]. ...
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 aim
To describe the multiple breath washout test, its applications to lung pathology and respiratory disease, as well as directions for future research.
... In individuals with mild CF lung disease, FEV 1 is less responsive to treatment [5]. The lung clearance index (LCI) derived from multiple breath inert gas washout (MBW) quantifies global ventilation inhomogeneity and is a sensitive biomarker of central and peripheral airway function [6]. ...
... There are several reasons why LCI should be further considered. and structural lung disease [4,6]. ...
Background: Lung clearance index (LCI) quantifies global ventilation inhomogeneity, a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease.
Objectives: We examined the association of LCI with the risk of death or lung transplantation (LTX) in individuals with CF.
Methods: We performed a retrospective analysis in a cohort of individuals with CF aged ≥ five years with available LCI and FEV1 measurements between 1980 and 2006. Outcome was time until death or LTX. We applied Cox proportional hazard regressions using the earliest available LCI and FEV1 values and adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1.
Results: In total, 237 individuals with CF aged mean (range) 13.9 (5.6-41.0) years were included. This time-to-event analysis accrued 3813 person-years, 94 (40%) individuals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01-1.06] per one z-score increase in LCI and 1.25 [1.11-1.41] per one z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01-1.07] for LCI, and 1.12 [0.95-1.33] for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations.
Conclusions: Increased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in individuals with CF.
... Abnormal LCI values can be detected in patients with CF shortly after birth [53], which corroborates the separate observations of early lung inflammation in the absence of infection [54]. LCI values are affected by infection status, with higher values being associated with Pseudomonas aeruginosa infection [40,58] and decreased bacterial diversity (a marker of more advanced disease in CF) [41]. LCI is sensitive to the effects of treatment, as demonstrated by improvement with hypertonic saline [35,38], dornase alfa [36], and CFTR modulators [37,55]. ...
... In terms of limitations, MBW testing is a time-consuming procedure and can be challenging to perform in very young or inexperienced children [40,43]. Real-world experience of the technique outside specialist centers remains limited, and the quality of LCI measurements is dependent on both the operator and the equipment [48,50]. ...
Introduction: In the early stages, lung involvement in cystic fibrosis (CF) can be silent, with disease progression occurring in the absence of clinical symptoms. Irreversible airway damage is present in the early stages of disease; however, reliable biomarkers of early damage due to inflammation and infection that are universally applicable in day-to-day patient management have yet to be identified.
Areas covered: At present, the main methods of detecting and monitoring early lung disease in CF are the lung clearance index (LCI), computed tomography (CT), and magnetic resonance imaging (MRI). LCI can be used to detect patients who may require more intense monitoring, identify exacerbations, and monitor responses to new interventions. High-resolution CT detects structural alterations in the lungs of CF patients with the best resolution of current imaging techniques. MRI is a radiation-free imaging alternative that provides both morphological and functional information. The role of MRI for short-term follow-up and pulmonary exacerbations is currently being investigated.
Expert opinion: The roles of LCI and MRI are expected to expand considerably over the next few years. Meanwhile, closer collaboration between pulmonology and radiology specialties is an important goal toward improving care and optimizing outcomes in young patients with CF.
... LCI values have been investigated in relation to cough swab and sputum culture results among CF patients (16,29,42,43). Patients with chronic lung infection with Aspergillus fumigatus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia had higher LCI levels than those with normal oral flora (44,45). ...
... Patients with chronic lung infection with Aspergillus fumigatus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia had higher LCI levels than those with normal oral flora (44,45). LCI values were associated with chronic infection with known CF pathogens (16) and pathogen load (42). Spirometry, LCI, and CT measures were all worse in patients colonized with P. aeruginosa compared to Staphylococcus aureus. ...
As Cystic Fibrosis (CF) treatment advances, research evidence has highlighted the value and applicability of Lung Clearance Index and Cardiopulmonary Exercise Testing as endpoints for clinical trials. In the context of these new endpoints for CF trials, we have explored the use of these two test outcomes for routine CF care. In this review we have presented the use of these methods in assessing disease severity, disease progression, and the efficacy of new interventions with considerations for future research.
... Similarly, LCI variability improves with age to a within-test CV (coefficient of variation) of 5.2% in preschoolers [50]. In a clinical study, it was possible to perform LCI examination in 90% of cases in the 4-16 age group, while 2 or more measurements were performed in 41% of cases [51]. ...
... LCI also requires some time to be performed, because repeated measurements may take several times to ensure reliable results. The reported average duration of a N 2 -MBW test in children with cystic fibrosis is 3.3 min (1.2 to 6.4), while it is 2.9 min (1.2-4.0) in controls [51]. ...
The Lung Clearance Index (LCI) is an index derived from washout recordings, able to detect early peripheral airway damage in subjects with cystic fibrosis (CF) with a greater sensitivity than spirometry.
LCI is a marker of overall lung ventilation inhomogeneity; in fact, as pulmonary ventilation worsens, the number of tidal breaths and the expiratory volumes required to clear the lungs of a marker gas are increased, as documented by a greater value.
In the field of CF, LCI allows indirect investigation of the small airways (< 2 mm) the site where, from a pathophysiologic point of view, the disease begins due to the defect of the CF transmembrane-conductance regulator (CFTR) protein. Infant pulmonary function changes seem to occur before clinically overt symptoms of lower respiratory illness occur.
When performing the test, it is important to refer to the American Thoracic Society and European Respiratory Society consensus statements and apply a strict standardization.
In Italy the first tests were carried out in 2014 for research purpose and now approximately 10 centers are collecting data and are experiencing a consistency in repeating exams.
Currently in Italian centers children at pre-school age are the main target: in this population it is important to have a sensitive and feasible test, non-invasive, that can be performed at tidal volume without sedation, and requiring minimal cooperation and coordination, and that can be used longitudinally over time. Another target could be the transplanted subjects to detect early signs of lung function decline.
The content of this paper captures the experience and discussions among some of the Italian centers where LCI is currently used for research and/or in clinical practice about the method and the need to have a common approach.
The aim of this paper is not to describe the methodology of MBW, but to inform the pediatric community about the possible application of LCI in CF.
... 9 N 2 -MBW tests were performed according to the European Respiratory Society (ERS) consensus and international standard operating procedures. 8,10 The main outcome was the LCI, a measure of global ventilation inhomogeneities. 10 Specific diffusion-and convection-dependent ventilation inhomogeneity was estimated by S cond and acinar ventilation inhomogeneity by S acin 10 from phase III slope analysis as recommended and described elsewhere. ...
... Results of our study confirm the findings of a low intra-test variability for LCI. 7,8,24,27 While S acin provides specific information 25 on lung compartments close to the acinar compartments 28 and good discrimination between patients and HC, 29 high variability may preclude its use as an end point in IPF. Further studies are needed to determine if S acin can be used to detect short-term changes in lung function at an early stage (e.g. at the beginning of acute exacerbations), which is a major challenge in IPF care. ...
Background and objective
Idiopathic pulmonary fibrosis (IPF) is a devastating progressive lung disease affecting the parenchyma. Nitrogen multiple‐breath washout (N2‐MBW) is a lung function test that measures ventilation inhomogeneity, a biomarker of small airway disease. We assessed clinical properties of N2‐MBW in IPF.
Methods
In this prospective cohort pilot study, 25 IPF patients and 25 healthy controls were assessed at baseline and 10 patients at median 6.2 months later. Outcomes included the lung clearance index (LCI) from N2‐MBW, forced vital capacity (FVC) from spirometry, diffusion capacity of the lungs for carbon monoxide (DLCO), bronchiectasis score from computed tomography scans, the Gender–Age–Physiology (GAP score for IPF) stage and death or lung transplantation (LTx). Study end points were feasibility, repeatability, discriminative capacity and correlation with disease severity and structural lung damage.
Results
All patients were able to perform N2‐MBW. LCI was repeatable and reproducible. Median (interquartile range (IQR)) LCI in IPF was 11.6 (10.1–13.8) in IPF versus 7.3 (6.9–8.4) in controls (P < 0.0001). LCI correlated with DLCO corrected for haemoglobin (corrDLCO; r = −0.49, P = 0.016), bronchiectasis score (r = 0.45, P = 0.024) and the GAP stage (r = 0.59, P = 0.002), but not with FVC. FVC was not related to bronchiectasis. During follow‐up, six patients died and one received LTx. LCI correlated with the latter compound outcome: hazard ratio (95% CI) was 2.43 (1.26; 4.69) per one LCI SD from the patient population.
Conclusion
N2‐MBW is a feasible, reliable and valid lung function test in IPF. LCI correlates with diffusion impairment, structural airway damage and clinical disease severity. LCI is a promising surveillance tool in IPF that may predict mortality.
... Another study found that LCI during preschool years was more likely to be abnormal than spirometry, and an abnormal LCI in preschool children predicted both abnormal LCI, and abnormal spirometry at school age [103]. Studies in infants [45], children [53,102] and adults [105] showed that patients with evidence of a bacterial infection were more likely to have abnormal LCI values. Findings from the longitudinal study AREST-CF suggested that LCI has a more pronounced increase in infants with airway infections compared with those without, and that this increase was long lasting [46]. ...
... Spirometry was rather insensitive in the assessment of peripheral airways, unless severe obstruction was present [119]. LCI in asthmatic subjects was slightly elevated compared with healthy controls, but often within the normal range, and therefore not helpful in the diagnosis of asthma Singer [53] 108 0.1-2.5 years Prospective LCI measurements at three time points during 2 years revealed a longlasting increase in LCI after pulmonary infections. Haemophilus influenzae infections had a particularly detrimental effect on lung function. ...
Multiple breath inert gas washout (MBW) is a lung function technique to measure ventilation inhomogeneity. The technique was developed more than 60 years ago, but not much used for many decades. Technical improvements, easy protocols and higher sensitivity compared with standard lung function tests in some disease groups have led to a recent renaissance of MBW. The lung clearance index (LCI) is a common measure derived from MBW tests, and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry. The LCI measures the overall degree of pulmonary ventilation inhomogeneity. There are other MBW-derived parameters, which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity. How this specific ventilation distribution is exactly related to different disease processes has not entirely been examined yet. MBW measurements are performed during tidal breathing, making this technique attractive for children, even young children and infants. These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW, especially in paediatric lung diseases such as cystic fibrosis (CF). In these patients, LCI detects early airway damage and enables monitoring of disease progression and treatment response. Guidelines for the standardisation of the MBW technique were recently published. These guidelines will, hopefully, increase comparability of LCI data obtained in different centres or intervention trials in children and adults. In this non-systematic review article, we provide an overview of recent developments in MBW, with a special focus on children. We first explain the physiological and technical background to this technique with a short explanation of several methodological aspects that are important for understanding the principle behind the technique and enable high quality measurements. We then provide examples of MBW application in different lung diseases of children and adults, with regards to both clinical application and research activities. Lastly, we report on ongoing clinical trials using MBW as outcome and give an outlook on possible future developments.
... Today, in the new period of CF care with the CFTR modulators, the progression of lung damage has slowed down [28] and FEV1 has become a less sensitive consequence measure. Although, FEV1 is associated with changes in central airways in CF patients with advanced lung disease, and many researchers have questioned its sensitivity in the early detection of lung damage [29,30], however, our study indicates that 12 patients ( 66.6%) of the 18 patients who were admitted for exacerbation had FEV1 <80.The reason for this discrepancy between our study and previous studies is probably the fact that some CF patients in the routine care, did not inhale albuterol before inhalation of 7% hypertonic saline, which can create bronchospasm and reduce FEV1 [31]. AS mentioned earlier P.aeruginosa was the common pathologic colonization in sputum culture in CF patients who were admitted for treatment with ceftazidime and amikacin [32]. ...
Background: The early determination and treatment of lung exacerbation have a significant role in increasing the health and quality of life in patients with cystic fibrosis. The Multiple-breath washout (MBW) technique was used to discriminate between health and disease of the lungs recently, however, its role in the prediction of upcoming exacerbation is not clear .This study aims to clarify this ambiguity.
Methods: We recruited 60 clinically stable children with cystic fibrosis who were coming to the CF clinic for periodic care. In addition to the routine pulmonary function tests (PFT), we performed MBW technique for all subjects as an annual assessment. Subsequently, in the follow-up period, we admitted all patients who had experienced exacerbation within two weeks after the MBWT for proper antimicrobial therapy. During admission, we reevaluated the PFT results of hospitalized subjects and compared them with the PFT results of subjects who had no exacerbation.
Results: Overall 55 subjects finished the trial; 18 cases (32.7%) were hospitalized and 37 patients (67.3%) were not hospitalized. The LCI5% variable had no significant difference between hospitalized and non-hospitalized groups. The median of the LCI2.5% in the hospitalized group (13.26) was greater than in the non-hospitalized group(7.82), this difference was statistically significant (P = 0.0001). The mean value of M2 /M0 in hospitalized patients (16.31) was greater than in non-hospitalized patients (5.97) and this difference was statistically significant (P = 0.0001).
Conclusion: Our study outcomes had a valuable ability to predict exacerbation, however, this hypothesis requires further studies with larger sample sizes.
... New PFTs correlated with structural changes have been recently investigated, including the multiple breath washout test, which allows the assessment of the lung clearance index (LCI). The LCI is a parameter of ventilatory inhomogeneity which is currently recognized as the most sensitive index for identifying small airway obstruction (43)(44)(45). Despite intraindividual variability of up to 15%, higher values of LCI may be a telltale sign of RTE (46,47). ...
Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective “cut-offs” for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient.
... Multiple breath washout. All participants performed three trials of standard N 2 MBW until 1/40th of initial starting end-tidal N 2 concentration according to the ERS consensus using an ultrasonic flowmeter equipment (Exhalyzer D, with Spiroware software, EcoMedics AG, Duernten, Switzerland) 28,29 . The resting time in between MBW trials was at least five minutes. ...
Patients with neuromuscular disease often suffer from weak and ineffective cough resulting in mucus retention and increased risk for chest infections. Different airway clearance techniques have been proposed, one of them being the insufflator/exsufflator technique. So far, the immediate physiological effects of the insufflator/exsufflator technique on ventilation distribution and lung volumes are not known. We aimed to describe the immediate effects of the insufflator/exsufflator technique on different lung volumes, forced flows and ventilation distribution. Eight subjects (age 5.8–15.2 years) performed lung function tests including spirometry, multiple breath washout and electrical impedance tomography before and after a regular a chest physiotherapy session with an insufflator/exsufflator device. Forced lung volumes and flows as well as parameters of ventilation distribution derived from multiple breath washout and electrical impedance tomography were compared to assess the short-term effect of the therapy. In this small group of stable paediatric subjects with neuromuscular disease we could not demonstrate any short-term effects of insufflation/exsufflation manoeuvres on lung volumes, expiratory flows and ventilation distribution. With the currently used protocol of the insufflation/exsufflation manoeuvre, we cannot demonstrate any immediate changes in lung function.
... The Forced Expiratory Volume in one second as a percent of the predicted value (FEV1%pred.) was determined with spirometry, and calculated according to reference values from the European Respiratory Society [34]. In addition, the lung clearance index (LCI), as a parameter to measure ventilation inhomogeneities in the small airways, was determined additionally with a multiple breath washout (MBW) test with N 2 as a tracer gas [35,36]. The normal values for the LCI 2.5% (hereafter referred to only as LCI) we used are reported to range from 6.16 to 7.91 for school-aged children 6 to 18 years of age [37]. ...
Chronic rhinosinusitis (CRS) is a characteristic feature of cystic fibrosis (CF) multiorgan disease and develops early in the life of patients with CF. The study aimed to correlate the inflammatory markers and the presence of structural abnormalities detected by MRI in the paranasal sinuses of patients with CF. Methods: Nasal lavage and MRI of the paranasal sinuses was performed in a cohort of 30 CF patients (median age 14 y; range 7–20 y). Morphological abnormalities characteristic of CF were evaluated with a dedicated CRS MRI scoring system and correlated with different inflammation parameters measured in nasal lavage. Inflammation of the paranasal sinuses was positively associated with structural abnormalities in MRI. The concentration of the pro-inflammatory markers neutrophil elastase (NE) and the neutrophil elastase/alpha1-antitrypsin (NE/A1AT) complex correlated significantly with CRS-MRI sum score (p < 0.05, r = 0.416 and p < 0.05, r = 0.366, respectively). S. aureus infection was associated with the increased pro-inflammatory cytokine activity of IL-6 and IL-8, and increased levels of NE/A1AT complex in our patients (p < 0.05, respectively). CRS-MRI sum score and individual sinus MRI scores were positively associated with inflammatory activity as a sign of CRS pathology present in CF.
... From a technical perspective, the test takes more time than spirometry to perform (to which it would be additional) and the equipment is poorly mobile, making the test difficult to integrate into multidisciplinary CF clinic scheduling. 14 Key clinical questions remain relating to natural variability in LCI, progression over time and what constitutes a minimally important clinical change in LCI within patients. ...
Background:
Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease.
Methods:
Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system.
Results:
112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1 z-score was -1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min.
Conclusions:
Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.
... Variability was high in all age groups with LCI z-scores ranging from −0.9 to 16.0 (age 0-1 years), −2.2 to 26.9 (age 2-5 years), −0.8 to 29.1 (age 6-11 years) and 1.0 to 26.7 (age 12-21 years) ( Figure 1A) [31]. Variability in LCI at an individual level within a group of investigated children of the same age that started in infancy and progressed during childhood has also been demonstrated by several other studies on CF lung disease [29,30,33,98,104,[108][109][110][111][112][113][114][115][116][117][118]. In addition, LCI has been used as an endpoint in studies investigating the efficacy of mucolytic therapies with hypertonic saline or rhDNase in CF from infancy to adolescence [25,28,101,102,107]. ...
Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.
... The LCI, measured by the multiple breath washout test, is a lung function outcome that has been shown to be more sensitive than spirometry, to correlate with airway changes seen on high-resolution computed tomography and to detect significant treatment effects in randomized controlled trials (Accurso et al., 2014;Aurora et al., 2004;Shaw et al., 2020;Singer et al., 2013;Spruit et al., 2013). A percentage change in LCI greater than ±15% in preschool children can be considered physiologically relevant and greater than the biological variability of the test (Oude Engberink et al., 2017). ...
Background
New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases.
Method
We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow‐up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found.
Conclusion
Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.
... MBW testing was performed with the Exhalyzer D system/spiroware 3 (Eco Medics) and 100% oxygen was used to wash out resident nitrogen from the lungs using a mouthpiece as an interface (14,(37)(38)(39) as detailed in the online supplement. ...
Rationale:
Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of cystic fibrosis transmembrane conductance regulator (CFTR) activity and moderate improvement of spirometry in Phe508del homozygous patients with cystic fibrosis (CF). However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown.
Objectives:
To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation.
Methods:
In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome and pro-inflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy.
Measurements and main results:
Lumacaftor-ivacaftor had no effects on FEV1 % predicted (1.7%, 95% confidence interval (CI) -1.0 to 4.3%; P = 0.211), but improved LCI (-1.6, 95% CI -2.6 to -0.5; P < 0.01) and MRI morphology (-1.3, 95% CI -2.3 to -0.3; P < 0.05) and perfusion score (-1.2, 95% CI -2.3 to -0.2; P < 0.05) in our study cohort. Further, lumacaftor-ivacaftor decreased the total bacterial load (-1.8, 95% CI -3.3 to -0.34; P < 0.05) and increased the Shannon diversity of the airway microbiome (0.4, 95% CI 0.1 to 0.8; P < 0.05), and reduced IL-1β levels (median change -324.2 pg/ml, 95% CI -938.7 to 290.4 pg/ml; P < 0.05) in sputum of Phe508del homozygous patients.
Conclusions:
This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV1 % predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).
... The new imaging technology with short duration of radiation exposure and the low radiation CF protocols are associated with minimal radiation. Furthermore, studies demonstrated that acute structural changes can be reversible when treated immediately [24][25][26][27][28][29][30] . The very strong correlation between LCI and Brody Score suggests that LCI can be used more frequently and as long as LCI levels remain normal, routine chest CT scans can be postponed to the time when levels of LCI become abnormal or deteriorate. ...
... In younger children, success is the norm above around 3 years old, but requires a controlled environment and an experienced team (32). Testing takes longer than spirometry, placing limitations on scale up to routine clinical use (55,56). ...
Purpose of review:
Early stage lung disease has long been synonymous with infancy and childhood. As diagnosis happens earlier and conventional management improves, we are seeing larger proportions of people with cystic fibrosis (CF) in adolescence and even adulthood with well preserved lung health. The availability of highly effective cystic fibrosis transmembrane conductance regulator modulator drugs for a large proportion of the CF population will impact even further. Transitioning into adult care with 'normal' lung function will become more common. However, it is crucial that we are not blasé about this phase, which sets the scene for future lung health. It is well recognized that lung function assessed by spirometry is insensitive to 'early' changes occurring in the distal, small airways. Much of our learning has come from studies in infants and young children, which have allowed assessment and optimization of alternative forms of monitoring.
Recent findings:
Here, as a group of paediatric and adult CF specialists, we review the evidence base for sensitive physiological testing based on multibreath washout, lung imaging, exercise and activity monitoring, assessment of infection and quality of life measures.
Summary:
We seek to emphasise the importance of further work in these areas, as outcome measures become widely applicable to a growing CF population.
... Finally, the clinical applicability could improve by enhancing the accessibility of the MBW technique, as MBW is not yet implemented on a large scale [27]. To date, several factors limit the use of MBW in clinical routine, and the European Respiratory Society/American Thoracic Society MBW consensus statement addresses, for example, the high proportion of test time consumption, the complexity of MBW equipment preparation and data processing as present day challenges [16]. ...
... Longer physiology testing times disrupt clinic scheduling and may not be tolerated by younger children. When researchers tried to limit the test time to 20 minutes using nitrogen washout in children with CF too few children obtained successful results, with the required minimum of two or more repeats achieved in only 40% of participants [20]. To enable the wider clinical adoption of LCI would require reduction in time taken to perform the test and increased flexibility in where testing occurs. ...
Introduction
Lung clearance index (LCI) is a sensitive measure of early lung disease, but adoption into clinical practice has been slow. Challenges include the time taken to perform each test. We recently described a closed-circuit inert gas wash-in method that reduces overall testing time by decreasing the time to equilibration. The aim of this study was to define a normative range of LCI in healthy adults and children derived using this method. We were also interested in the feasibility of using this system to measure LCI in a community setting.
Methods
LCI was assessed in healthy volunteers at three hospital sites and in two local primary schools. Volunteers completed three washout repeats at a single visit using the closed circuit wash-in method (0.2% SF6 wash-in tracer gas to equilibrium, room air washout).
Results
160 adult and paediatric subjects successfully completed LCI assessment (95%) (100 in hospital, 60 in primary schools). Median coefficient of variation was 3.4% for LCI repeats and 4.3% for FRC. Mean (SD) LCI for the analysis cohort (n = 53, age 5–39 years) was 6.10 (0.42), making the upper limit of normal LCI 6.8. There was no relationship between LCI and multiple demographic variables. Median (interquartile range) total test time was 18.7 (16.0–22.5) minutes.
Conclusion
The closed circuit method of LCI measurement can be successfully and reproducibly measured in healthy volunteers, including in out-of-hospital settings. Normal range appears stable up to 39 years. With few subjects older than 40 years, further work is required to define the normal limits above this age.
... Importantly, we have also shown that LCI is feasible in an outpatient setting using a novel rapid wash-in method, and that this allows measurements to be completed in <30 mins with high success rates and within-visit repeatability. Measurement times and repeatability are as good as or better than those reported for LCI in other populations [10,19,20]. These are important initial steps in establishing LCI as an outcome measure for post-transplant monitoring of OB. ...
Background
Long-term outcomes after lung transplantation are often limited by the development of obliterative bronchiolitis (OB), which is clinically defined using spirometry as bronchiolitis obliterans syndrome (BOS). Lung clearance index (LCI), derived from multiple breath washout (MBW) testing, is a global measure of ventilation heterogeneity that has previously been shown to be a more sensitive measure of obstructive small airway diseases than spirometry. We aimed to assess the feasibility of LCI in adult lung transplant patients and to compare LCI to BOS grade.
Methods
51 stable adult double-lung transplant recipients performed sulfur hexafluoride MBW in triplicate on a single occasion, using a closed-circuit Innocor device. BOS grades were derived from serial spirometry according to International Society for Heart and Lung Transplantation criteria and, where available, high-resolution computed tomography (HRCT) evidence of OB was recorded.
Results
LCI was successfully performed in 98% of patients. The within-visit coefficient of variation for repeat LCI measurements was 3.1%. Mean LCI increased significantly with BOS grades: no BOS (n=15), LCI 7.6; BOS-0p (n=16), LCI 8.3; BOS-1 (n=11), LCI 9.3; BOS-2–3 (n=9), LCI 13.2 (p<0.001). 27 patients had HRCT within 12 months. LCI in those with HRCT evidence of OB was higher than those without OB (11.1 versus 8.2, p=0.006). 47% patients displayed abnormal LCI (>7) despite a normal forced expiratory volume in 1 s (FEV 1 ) (>80% of baseline).
Conclusions
LCI measurement in lung transplant recipients is feasible and reproducible. LCI increased with increasing BOS grade. A significant proportion of this cohort had abnormal LCI with preserved FEV 1 , suggesting early subclinical small airway dysfunction, and supporting a role for MBW in the early identification of BOS.
... These observations indicate that the absolute change of LCI > 1 unit represents a clinical relevant change [17] . Likewise, Singer et al [18] found that the coefficient of repeatability between tests occasions performed 24 h apart, was 0.96 in children with CF compared to 0.62 in controls. Their results also indicate that a change of LCI of at least 1 unit is clinically meaningful in children with CF. ...
A sensitive, reproducible and feasible measure of lung function for monitoring the respiratory health is a prerequisite for the optimization of management of the patients with cystic fibrosis (CF). Spirometry has been considered the method of choice, although it is applicable only in children older than 6 years of age, as good cooperation is necessary for its proper performance. However, over the last 15 years, scientific interest in gas dilution techniques and particularly in multiple breath wash out (MBW) method has been revived. The most commonly reported index of MBW is lung clearance index (LCI). The aim of this review is to present the most recent developments in the application of LCI as a monitoring index of respiratory status of CF patients. LCI is a sensitive and reproducible marker of ventilation inhomogeneity. It is more sensitive than spirometry and, unlike spirometry; it can be performed across the whole pediatric age range. Since it is dependent on body size, until at least the age of 6 years, the relative and not the absolute changes are more appropriate for providing clinically meaningful conclusion on ventilation inhomogeneity. Until now, MBW has been mainly used as a research tool. Based on the currently available data LCI cannot safely predict high-resolution computed tomography findings in children with CF, especially in infants. It can be used as an end-point measure for the assessment of beneficial effect of interventions. However, its utility as an outcome measure for the efficacy of therapeutic interventions seems to be dependent on the pathophysiologic mechanisms that underlie each intervention. It seems that more studies, especially longitudinal ones, are required in order to fully clarify the clinical usefulness of LCI, not only in the research setting, but also in every day practice of CF clinic.
... Application of strap resting period: 15 min without restriction EIT (20) Restricted N2MBW (20), EIT (19), spirometry (20), body plethysmography (20) Baseline 2 N2MBW (19), EIT (19), spirometry (20), body plethysmography (20) Pulmonary Function Tests Nitrogen Multiple-Breath Washout All participants performed standard N 2 MBW until 1/40th of initial starting end-tidal N 2 concentration according to the ERS consensus using an ultrasonic flowmeter (Exhalyzer D, with Spiroware software, EcoMedics AG, Duernten, Switzerland) [14][15][16]. MBW assesses the efficiency of ventilation distribution by estimating the breathing effort required to washout resident N 2 gas from the lungs during tidal breathing of 100% oxygen [15]. Outcomes were LCI, FRC MBW , S cond , and S acin . ...
Background:
Elastic chest wall restriction introduced by Chevaillier is thought to reduce existing hyperinflation and improve mucus clearance from peripheral airways. In healthy adults, restriction decreases the functional residual capacity (FRC) and forced vital capacity (FVC), while ventilation inhomogeneity (lung clearance index [LCI]) increases. Pulmonary function response to restriction is unknown in individuals with cystic fibrosis (CF).
Objectives:
To examine short-term effects of elastic chest wall restriction on pulmonary function in children with CF.
Methods:
Pulmonary function was first assessed twice 15 min apart at baseline and then again following 15 min of elastic chest wall restriction in 20 school-aged children with CF (12.3 ± 3.4 years). Primary outcomes were LCI from nitrogen multiple-breath washout, residual volume (RV), and FRC from plethysmography. Secondary outcomes were FVC and end-expiratory lung impedance (EELI) from electrical impedance tomography. Endpoints were test-retest reliability at baseline and lung function response to restriction, both on group and individual levels.
Results:
Test-retest reliability was excellent (intra-class correlation coefficients range 0.84-0.99). Following restriction, FRC significantly declined on average (95% CI) by -0.09 (-0.17 to -0.02) L. Similarly, FVC declined while LCI did not change. RV and EELI declined, but this did not reach statistical significance. On the individuals' level, heterogeneous changes in pulmonary function occurred following elastic chest wall restriction.
Conclusions:
These findings indicate that the application of elastic chest wall restriction is safe, induces the intended decline in resting lung volume but does not systematically alter ventilation inhomogeneity in children with CF.
... Eco Medics AG). During the test children were sitting upright, wearing a nose clip and breathing tidally through a snorkel mouthpiece, as previously described [14]. ...
Lung clearance index (LCI) is the main outcome of the multiple-breath washout (MBW) test. Current recommendations for LCI acquisition are based on low-grade evidence. The aim of this study was to challenge those recommendations using alternative methods for LCI analysis.
Nitrogen MBW measurements from school-aged children, 20 healthy controls, 20 with cystic fibrosis (CF) and 17 with primary ciliary dyskinesia (PCD), were analysed using 1) current algorithms (standard), 2) three alternative algorithms to detect with higher precision the end of MBW testing and 3) two alternative algorithms to determine exhaled tracer gas concentrations. LCI values, intra-test repeatability, and ability to discriminate between health and lung disease were compared between these methods.
The analysis methods strongly influenced LCI (mean±sd overall differences (%) between standard and alternative analysis methods: −4.9±5.7%; range: −66–19%), but did not improve intra-test variability. Discrimination between health and disease was comparable as areas under the receiver operator curves were not greater than that from standard analysis.
This study supports current recommendations for LCI calculation in children. Alternative methods influence LCI estimates and hamper comparability between MBW setups. Alternative algorithms, whenever used, should be carefully reported.
... However, LCI may be a valuable tool to investigate ongoing symptoms or as an outcome in clinical research studies (80). At present MBW is not routinely used in clinical practice but in centers where this technique is regularly performed an increase of 1 unit in the LCI value is considered a sign of pulmonary deterioration (82). As shown in the only published reference equations, LCI is dependent on body size and decreases as height increases, particularly in early childhood. ...
Pulmonary function tests are routinely used in the diagnosis and follow-up of respiratory diseases. In preschool children assessment and evaluation of lung function has always been challenging but improved techniques that require only minimal collaboration allowed obtaining reliable and useful results even in this group of patients. In this review we will describe the different techniques used in clinical practice to measure lung function in preschool children.
... JENSEN et al. [14] compared the N 2 -MBW and SF 6 -MBW data in children aged 3-18 years and nitrogen washout proved as a feasible alternative to SF 6 washout with similar discriminative power and repeatability. Our data on repeatability of N 2 -MBW in infants are comparable to the data of SINGER et al. [15] from older children. We obtained lower coefficient of variation of LCI in infants, while coefficient of repeatability was slightly higher. ...
... Le LCI est mesuré par dosage des gaz dans la respiration spontanée, c'est un témoin de l'homogénéité ventilatoire des poumons. Cette méthode est plus sensible que les examens conventionnels de la fonction pulmonaire (spirométrie, pléthysmographie du corps entier, etc.) pour les atteintes pulmonaires initiales de la CF [3,4]. Pour les deux enfants porteurs de la mutation G551D, l'assurance-invalidité (AI) a accepté de prendre en charge les coûts de traitement en novembre 2013, soit avant l'admission de Kalydeco ® par Swissmedic en janvier 2014. ...
... The 2014 review concluded that LCI has a low variability between repeated sessions (i.e. stable coefficient of variation [CV%]) with one study reporting a coefficient of reproducibility (COR) of 0.96 for measurements 24 hours apart (using MBN 2 W and an Exhalyzer D a ) [5]. There have been more limited data on the longer term inter-test repeatability within the CF population, thus the interpretation of a clinically meaningful change is more difficult. ...
... The moderate strength of correlations with LCI were similar to that observed with FEV1 % pred. The results from this study including older children and adults are in agreement with studies in infants and younger children reporting a significant relationship between elevated LCI and the presence of lower respiratory tract infection [12,13] and specifically between LCI and P. aeruginosa infection [11,17,18]. Furthermore, these data show that LCI is elevated in individuals with infection with other pathogens including S. aureus, S. maltophilia and H. influenzae, whereas FEV1 % pred showed no difference. ...
... Hence, we defined a change in LCI > 0.7 during the day as being clinically significant. As in previous studies [4][5][6], we expected CPT to have a greater impact on LCI and defined a clinically meaningful effect by CPT as a change in LCI > 1 [20]. The calculation was based on the study design in Fig 2 and on the use of a linear mixed model with a random intercept for each child (with a variance of 2.75) and an interaction between child and visit to account for the nested design. ...
In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW) measures in children with clinically stable cystic fibrosis. To our knowledge the effect of time-of-day on multiple breath washout measures in patients with cystic fibrosis has not previously been reported. Furthermore, we assessed the influence of chest physiotherapy on N2MBW measures.Ten school children with cystic fibrosis performed N2MBW followed by spirometry and plethysmography in the morning and afternoon at three visits that were one month apart. Chest physiotherapy was performed immediately before the afternoon measurements at visit 2 and immediately before morning and afternoon measurements at visit 3. The influence of time-of-day and chest physiotherapy on the measures was evaluated using linear mixed models.There were adequate quality data from 8 children with median age (range) 9.6 (6.0; 15.1) years. Baseline lung clearance index (LCI) (range) was 9.0 (7.1; 13.0) and baseline FEV1% predicted was 97.5 (78.5; 117.9). No N2MBW measures were significantly influenced by time-of-day or chest physiotherapy. LCI (95% confidence interval) decreased non-significantly 0.05 (-0.32; 0.22) during the day and increased non-significantly 0.08 (-0.26; 0.42) after chest physiotherapy. All spirometric measures were unaffected by time-of-day and chest physiotherapy. For plethysmographic measures FRCpleth decreased significantly (p
... Early diagnosis by newborn screening and improvement of therapy has raised interest in diagnostic tools to detect lung function impairment early and prior to irreversible lung damage [2][3][4]. Current techniques such as nitrogen multiple-breath washout (N 2 -MBW) or high-resolution computer tomography (HRCT) allow monitoring of early lung disease [5,6]. However, both techniques are constrained by methodological drawbacks. ...
Lung function tests are commonly used to monitor lung disease in cystic fibrosis (CF). While practical, they cannot locate the exact origin of functional impairment. Contemporary magnetic resonance imaging (MRI) techniques provide information on the location of disease but the need for contrast agents constrains their repeated application. We examined the correlation between functional MRI, performed without administration of contrast agent, and lung clearance index (LCI) from nitrogen multiple-breath washout (N 2 -MBW).
40 children with CF (median (range) age 12.0 (6–18) years) and 12 healthy age-matched controls underwent functional and structural MRI and lung function tests on the same day. Functional MRI provided semiquantitative measures of perfusion ( RQ ) and ventilation ( RFV ) impairment as percentages of affected lung volume. Morphological MRI was evaluated using CF-specific scores. LCI measured global ventilation inhomogeneity.
MRI detected functional impairment in CF: RFV 19–38% and RQ 16–35%. RFV and RQ correlated strongly with LCI (r=0.76, p<0.0001 and r=0.85, p<0.0001, respectively), as did total morphology score (r=0.81, p<0.0001). All indices differed significantly between patients with CF and healthy controls (p<0.001).
Noninvasive functional MRI is a promising method to detect and visualise perfusion and ventilation impairment in CF without the need for contrast agents.
... By measuring the efficiency of the lungs to clear out a marker gas, MBW depicts ventilation distribution inhomogeneity in the lungs [8], with the lung clearance index (LCI) being the most commonly reported outcome [9]. As peripheral CF lung pathology results in ventilation inhomogeneity early in the course of the disease [10], before any change in spirometry [11], LCI is considered the most sensitive lung function marker of mild CF lung disease [12]. ...
It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.
We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.
We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02–0.60; p=0.034 and 14.5 mL, 95% CI 7.7–21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.
Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.
Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown.
Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2–11 years before and 8–16 weeks after treatment initiation.
Results: A total of 13 children with CF homozygous for F508del aged 2–11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L ( p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal ( p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older.
Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2–11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters.
Background
Lung disease as major cause for morbidity in patients with cystic fibrosis (CF) starts early in life. Its large phenotypic heterogeneity is partially explained by the genotype but other contributing factors are not well delineated. The close relationship between mucus, inflammation and infection, drives morpho-functional alterations already early in pediatric CF disease, The TRACK-CF cohort has been established to gain insight to disease onset and progression, assessed by lung function testing and imaging to capture morpho-functional changes and to associate these with risk and protective factors, which contribute to the variation of the CF lung disease progression.
Methods and design
TRACK-CF is a prospective, longitudinal, observational cohort study following patients with CF from newborn screening or clinical diagnosis throughout childhood. The study protocol includes monthly telephone interviews, quarterly visits with microbiological sampling and multiple-breath washout and as well as a yearly chest magnetic resonance imaging. A parallel biobank has been set up to enable the translation from the deeply phenotyped cohort to the validation of relevant biomarkers. The main goal is to determine influencing factors by the combined analysis of clinical information and biomaterials. Primary endpoints are the lung clearance index by multiple breath washout and semi-quantitative magnetic resonance imaging scores. The frequency of pulmonary exacerbations, infection with pro-inflammatory pathogens and anthropometric data are defined as secondary endpoints.
Discussion
This extensive cohort includes children after diagnosis with comprehensive monitoring throughout childhood. The unique composition and the use of validated, sensitive methods with the attached biobank bears the potential to decisively advance the understanding of early CF lung disease.
Ethics and trial registration
The study protocol was approved by the Ethics Committees of the University of Heidelberg (approval S-211/2011) and each participating site and is registered at clinicaltrials.gov (NCT02270476).
Objectives:
To describe the short- and medium-term repeatability of lung clearance index (LCI2.5 ) in infants and calculate the number of patients needed to enrol in a study (N) using LCI2.5 as a primary outcome.
Methods:
An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated.
Results:
Forty infants with CF and 21 with RW were enrolled. Initial N2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI2.5 value. In clinically stable patients, LCI2.5 did not significantly change during the 8-month follow-up. Mean LCI2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intra-group differences of LCI2.5 and minimal difference to be detected would be 2.0.
Conclusion:
N2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies. This article is protected by copyright. All rights reserved.
Background:
The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease.
Objectives:
We examined the association of LCI with the risk of death or lung transplantation (LTX) in individuals with CF.
Methods:
We performed a retrospective analysis in a cohort of individuals with CF aged≥5 years with LCI and FEV1 measurements performed between 1980 and 2006. The outcome was time until death or LTX. We used the earliest available LCI and FEV1 values in a Cox proportional hazard regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1.
Results:
In total, 237 individuals with CF with a mean (range) age of 13.9 (5.6-41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01-1.06] per one z-score increase in LCI and 1.25 [1.11-1.41] per one z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01-1.07] for LCI, and 1.12 [0.95-1.33] for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations.
Conclusions:
Increased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in individuals with CF.
Background
Normal values (>80%) of Forced Expiratory Volume in one second (FEV1) in patients with Cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1.
Methods
Patients were recruited from two CF Centers: Hadassah Medical Center, Jerusalem and Vall d' Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT‐Brody Score, respiratory cultures, number of pulmonary exacerbations (PEx) and days of antibiotic treatment in the year prior to the assessment.
Results
Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age 17.6 range 4.25‐49 years). Chronic P. aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year prior to the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52‐18.97, and total Brody score (TBS) was abnormal in 92% (range 5.0‐96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p=0.01) and TBS (p=0.02) which were associated with more major PEx (p<0.01 and p=0.01, respectively) and more days of intravenous (IV) antibiotic treatment in the preceding year (p=0.03 and p=0.001, respectively).
Conclusions
Most CF patients with normal FEV1 have already physiological and structural lung abnormalities which were associated with more PEx and IV antibiotic treatment. Further studies are needed in order to determine if better adherence to the currently used therapies and the new CFTR modulators will prevent the progression of lung disease.
This article is protected by copyright. All rights reserved.
Background
The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis (CF). While LCI worsens during the preschool years in CF, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.
Methods
A cohort of children (healthy (HC) and CF) previously studied for 12 months as preschoolers were followed during school age (5–10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer® D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.
Results
A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 CF subjects were available. The majority of children with CF had elevated LCI at the first preschool and first school age visits (57.8% (37/64)), whereas all but six had normal forced expiratory volume in 1 s (FEV 1 ) values at the first school age visit. During school age years, the course of disease was stable (−0.02 units·year ⁻¹ (95% CI −0.14; 0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV 1, at school age.
Conclusion
Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.
Background
Lung clearance index (LCI) is a promising lung function outcome in individuals with primary ciliary dyskinesia (PCD). The impact of events clinically important for individuals with PCD, such as pulmonary exacerbations, on LCI is unknown.
Methods
We conducted an international, multicentre, observational cohort study to assess the association of LCI and risk of pulmonary exacerbation, specific changes in LCI during pulmonary exacerbation and global variability of LCI across four visits every 4 months. Ninety individuals with PCD, aged 3–41 years, underwent nitrogen multiple-breath washout (MBW) and spirometry measurements. The association of LCI and pulmonary exacerbations was assessed by Cox proportional hazards and random-effects regression models.
Results
We obtained 430 MBW and 427 spirometry measurements. In total, 379 person-years at risk contributed to the analysis. Per one unit increase (deterioration) in LCI, the risk of future pulmonary exacerbation increased by 13%: HR (95% CI), 1.13 (1.04 to 1.23). If LCI changed from a range of values considered normal to abnormal, the risk of future pulmonary exacerbations increased by 87%: 1.87 (1.08 to 3.23). During pulmonary exacerbations, LCI increased by 1.22 units (14.5%). After pulmonary exacerbations, LCI tended to decline. Estimates of variability in LCI suggested lower variation within individuals compared with variation between individuals. Findings were comparable for forced expiratory volume in 1 s.
Conclusion
On a visit-to-visit basis, LCI measurement may add to the prediction of pulmonary exacerbations, the assessment of lung function decline and the potential lung function response to treatment of pulmonary exacerbations.
Rationale
While lung clearance index (LCI) is a sensitive marker of small airway disease in individuals with cystic fibrosis (CF), less is known about longitudinal changes in LCI during routine clinical surveillance.
Objectives
To describe the longitudinal course of LCI in children with CF during routine clinical surveillance and assess influencing factors.
Methods
Children with CF aged 3–18 years performed LCI measurements every 3 months as part of routine clinical care between 2011 and 2018. We recorded clinical data at every visit. We used a multilevel mixed-effect model to determine changes in LCI over time and identify clinical factors that influence LCI course.
Measurements and Main Results
We collected LCI from 1204 visits (3603 trials) in 78 participants, of which 907 visits had acceptable LCI data. The average unadjusted increase in LCI for the entire population was 0.29 LCI units·year ⁻¹ (95% CI 0.20–0.38). The increase in LCI was more pronounced in adolescence, with 0.41 units·year ⁻¹ (95% CI 0.27–0.54). Colonisation with either Pseudomonas aeruginosa or Aspergillus fumigatus, pulmonary exacerbations, CF-related diabetes, and bronchopulmonary aspergillosis were associated with a higher increase in LCI over time. Adjusting for clinical risk factors reduced the increase in LCI over time to 0.24 LCI units·year ⁻¹ (95% CI 0.16–0.33).
Conclusion
LCI measured during routine clinical surveillance is associated with underlying disease progression in children with CF. An increased change in LCI over time should prompt further diagnostic intervention.
Background
Increased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function.
Methods
This was an international, multi-center, cross-sectional study. We collated data from individuals aged 3–25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding.
Results
We included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV1.
Conclusion
Increased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait.
Background
The nitrogen multiple breath washout (N 2 MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N 2 MBW outcomes in a cohort of healthy Caucasian school-aged children.
Methods
N 2 MBW data from healthy Caucasian school-age children between 6 and 18 years were collected from four experienced centers. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analyzed with commercial software (Spiroware, 3.2.1, Eco Medics AG). Normative values and upper limits of normal were generated for lung clearance index at 2.5% (LCI 2.5% ) and at 5% (LCI 5% ), moment ratios (M 1 /M 0 and M 2 /M 0 ), and a prediction equation generated for functional residual capacity (FRC).
Results
Four hundred and eighty five trials from 180 healthy Caucasian children aged from 6 to 18 years were used for analysis. While LCI increased with age, this increase was negligible (0.04 units/year for LCI 2.5% ) and therefore fixed upper limits of normal were defined for this age group. These limits were 7.91 for LCI 2.5% , 5.73 for LCI 5% , 1.75 for M 1 /M 0 , and 6.15 for M 2 /M 0 respectively. Height and weight were found to be independent predictors of FRC.
Conclusion
We report reference values for N 2 MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.
Background
Chronic lung diseases such as cystic fibrosis (CF) can be monitored by imaging and lung function modalities. Magnetic resonance imaging (MRI) techniques such as matrix pencil (MP) decomposition allows for evaluation of regional impairment of fractional ventilation (RFV) and relative perfusion (RQ). However, reproducibility of MP MRI outcomes in children with CF is unknown. We examined short-term variability of ventilation and perfusion impairment from MP MRI and compared this to lung function outcomes.
Method
Twenty-threeCF and 12 healthy school-aged children underwent MRI and lung function tests on the same day on two occasions 24 h apart. Global ventilation inhomogeneity was assessed by the lung clearance index (LCI) from nitrogen-multiple breath washout (N2-MBW) technique. Intra-class-coefficient (ICC), percentage change, and Bland-Altman limits of agreement were evaluated to assess reproducibility.
Results
Sixty-nine measurements from MP MRI and N2-MBW were performed. The ICC between two visits for RFV, RQ and LCI ranged between 0.60 and 0.90 in individuals with CF and healthy controls. In individuals with CF, percentage of change between the visits was 0.02% for RFV, −1.11% for RQ and 2.91% for LCI and limits of agreement between visits were − 4.3% and 3.9% for RFV, −4.4% and 3.7% for RQ, and −2.6 and 3.0 for LCI.
Conclusions
Functional imaging is reproducible and short-term changes in RFV and RQ greater than ±4.4% can be considered clinical meaningful. Very good short-term reproducibility, and easy application without the need for breathing maneuvers or contrast agent, makes MP MRI a promising surveillance method for CF.
1 Background
Childhood cancer survivors are at increased risk for pulmonary morbidity and mortality. International guidelines recommend pulmonary function tests (PFT) during follow‐up care. This nationwide study assessed how many children received PFT within 5 years after pulmotoxic treatment in Switzerland, types of tests, and predictors for testing.
2 Methods
We included all children from the Swiss Childhood Cancer Registry who were diagnosed with cancer from 1990 to 2013 at age 0–16 years, survived for ≥2 years from diagnosis, and had pulmotoxic chemotherapy with bleomycin, busulfan, nitrosoureas, and/or chest radiotherapy. We searched medical records in all Swiss pediatric oncology clinics for PFT (spirometry, plethysmography, diffusion capacity of carbon monoxide [DLCO]) and treatment details.
3 Results
We found medical records for 372 children, of whom 147 had pulmotoxic chemotherapy and 323 chest radiotherapy. Only 185 had plethysmography and/or spirometry (50%), 122 had DLCO (33%). Testing varied by cancer center from 3% to 79% (P = 0.001). Central nervous system tumor survivors and those not treated according to study protocols had less plethysmography and/or spirometry (odds ratio (OR) 0.3 and 0.3), lymphoma survivors and those who were symptomatic had more PFT (plethysmography and/or spirometry: OR 5.9 and 8.7; DLCO: OR 3.4 and 2.3). Cumulative incidence (CuI) of PFT was 52% in the first 5 years after pulmotoxic treatment; most of the tests were done in the first 2 years after treatment (CuI 44%).
4 Conclusion
Only half of the survivors exposed to pulmotoxic treatment have been followed up with PFT in Switzerland. We need to optimize, update, and implement monitoring guidelines.
Nitrogen multiple-breath washout (N2MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity.
We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N2MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N2MBW measurements performed by one healthy adolescent.
All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different “red flags”, i.e. signs that enable easy identification of leaks during measurements.
Air leaks during measurement significantly influence N2MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise.
For reliable assessment of ventilation inhomogeneity, multiple-breath washout (MBW) systems should be realistically validated. We describe a new lung model for in vitro validation under physiological conditions and the assessment of a new nitrogen (N(2))MBW system.
The N(2)MBW setup indirectly measures the N(2) fraction (F(N2)) from main-stream carbon dioxide (CO(2)) and side-stream oxygen (O(2)) signals: F(N2) = 1-F(O2)-F(CO2)-F(Argon). For in vitro N(2)MBW, a double chamber plastic lung model was filled with water, heated to 37°C, and ventilated at various lung volumes, respiratory rates, and F(CO2). In vivo N(2)MBW was undertaken in triplets on two occasions in 30 healthy adults. Primary N(2)MBW outcome was functional residual capacity (FRC). We assessed in vitro error (√[difference](2)) between measured and model FRC (100-4174 mL), and error between tests of in vivo FRC, lung clearance index (LCI), and normalized phase III slope indices (S(acin) and S(cond)).
The model generated 145 FRCs under BTPS conditions and various breathing patterns. Mean (SD) error was 2.3 (1.7)%. In 500 to 4174 mL FRCs, 121 (98%) of FRCs were within 5%. In 100 to 400 mL FRCs, the error was better than 7%. In vivo FRC error between tests was 10.1 (8.2)%. LCI was the most reproducible ventilation inhomogeneity index.
The lung model generates lung volumes under the conditions encountered during clinical MBW testing and enables realistic validation of MBW systems. The new N(2)MBW system reliably measures lung volumes and delivers reproducible LCI values.
Unrecognized airway infection and inflammation in young children with cystic fibrosis (CF) may lead to irreversible lung disease; therefore early detection and treatment is highly desirable.
To determine whether the lung clearance index (LCI) is a sensitive and repeatable noninvasive measure of airway infection and inflammation in newborn-screened children with CF.
Forty-seven well children with CF (mean age, 1.55 yr) and 25 healthy children (mean age, 1.26 yr) underwent multiple-breath washout testing. LCI within and between-test variability was assessed. Children with CF also had surveillance bronchoalveolar lavage performed.
The mean (SD) LCI in healthy children was 6.45 (0.49). The LCI was higher in children with CF (7.21 [0.81]; P < 0.001). The upper limit of normal for the LCI was 7.41. Fifteen (32%) children with CF had an elevated LCI. LCI measurements were repeatable and reproducible. Airway infection was present in 17 (36%) children with CF, including 7 (15%) with Pseudomonas aeruginosa. Polymicrobial growth was associated with worse inflammation. The LCI was higher in children with Pseudomonas (7.92 [1.16]) than in children without Pseudomonas (7.02 [0.56]) (P = 0.038). The LCI correlated with bronchoalveolar lavage IL-8 (R(2) = 0.20, P = 0.004) and neutrophil count (R(2) = 0.21, P = 0.001). An LCI below the upper limit of normality had a high negative predictive value (93%) in excluding Pseudomonas.
The LCI is elevated early in CF, especially in the presence of Pseudomonas and airway inflammation. The LCI is a feasible, repeatable, and sensitive noninvasive marker of lung disease in young children with CF.
In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF.
Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M(1)/M(0) and M(2)/M(0), respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping.
Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M(2)/M(0) but not LCI or M(1)/M(0). There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes.
These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.
High resolution computed tomography (HRCT) is a more sensitive tool for detecting early cystic fibrosis (CF) lung disease than either spirometry or plain radiography, but its relationship to other measures of lung function has not been established in young children.
(1) To assess whether the lung clearance index (LCI) derived from multiple breath inert-gas washout (MBW) is as effective as HRCT in identifying pulmonary abnormalities; and (2) explore the relationships between abnormalities detected by HRCT and by spirometry, plethysmography and MBW (collectively, LFTs) in young children with CF.
Children with CF underwent LFTs and volumetric HRCT on the same day. Healthy age-matched controls underwent identical LFTs without HRCT. Scans were anonymised, and scored using the Brody-II CT scoring system, to assess for presence and extent of bronchiectasis, airway wall thickening, mucus plugging, and parenchymal opacities.
Assessments were undertaken in 60 children with CF (mean (SD) 7.8 (1.3 years) and 54 healthy controls (7.9 (1.2) y). Among children with CF, 84% (47/56) had abnormal LCI, 58% (27/47) abnormal plethysmographic lung volumes (FRC(pleth) or RV), 35% (21/60) abnormal sRaw and 47% (28/60) abnormal spirometry (FEV1 or FEF(25-75)); whereas HRCT scans were abnormal in 85% (51/60): median total Brody-II score: 9.5% (range 0-51%). Total CT score correlated more strongly with LCI (Spearman correlation = 0.77) than with spirometry (R = -0.43) or any other marker of lung function. Of the nine children with normal LCI, five had abnormalities on HRCT, whereas five children with normal HRCT had raised LCI.
These results suggest that while LCI and HRCT have similar sensitivity to detect CF lung disease, complimentary information may be gained in individual patients.
The timely coordination of care in clinics that require frequent assessments by multiple specialists can be challenging for both patients and providers. The cornerstone of care at cystic fibrosis (CF) centers with superior clinical outcomes, as with reduced acuity of episodic disease and incidence of hospitalizations, is frequent clinical encounters coupled with aggressive therapies. However, inefficiencies in the clinical practice structure prevent optimal utilization of resources. To decrease non-value-added time, defined as time a patient spends alone in an examination room, without altering the time providers spend caring for a patient, the application of Lean methods was used to see whether reducing variation could significantly decrease lead time, considered the length of a patient visit, within a CF clinic setting. Baseline capability analyses revealed only 19.3% of patient visits were completed in 60min or less, with mean and median visit times of 84 and 81min, respectively. Final capability analyses demonstrated that 41.5% of patient visits were completed in 60min or less, 23% greater than the baseline capability. Mean and median visit times decreased by 10min per visit. Research efforts increased the available capacity by 500 patient visits per year, representing additional revenue of over US$165,000 annually with no additional administrative costs incurred.
The markedly improved life expectancy of children with cystic fibrosis (CF) has created a new challenge, as traditional markers of lung disease are frequently normal in young children. This prevents identification of individuals who may benefit from more aggressive therapy and also obliges large study numbers and prolonged duration for intervention studies. There is an urgent need for alternative surrogates that detect early lung disease and track through early childhood.
This study aimed to determine whether multiple-breath washout (MBW) results at preschool age can predict subsequent abnormal lung function.
Preschool children (3-5 yr) with CF and healthy control subjects underwent spirometry and MBW with testing repeated during early school age (6-10 yr). Primary outcomes were FEV1 from spirometry and lung clearance index (LCI) from MBW.
Forty-eight children with CF and 45 healthy children completed testing. Thirty-five (73%) children with CF had abnormal LCI at preschool age, whereas only five had abnormal FEV1. The positive predictive value of preschool LCI for predicting any abnormal school-age result was 94%, with a negative predictive value of 62%. Only one child with abnormal FEV1 at school age had had a normal preschool LCI. In contrast, for preschool FEV1 the positive predictive value was 100%, but negative predictive value was only 25%.
This study demonstrates that an abnormal preschool LCI predicts subsequent lung function abnormalities, whereas a normal preschool LCI usually remains normal. MBW has potential as a clinical and research outcome in young children with CF.
Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry.
CF patients between 6–18 yrs of age with FEV 1 ≥80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used.
The mean± sd age was 10.32±3.35 yrs. Dornase alfa improved LCI versus placebo (0.90±1.44; p = 0.022). Forced expiratory flow at 25–75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1%±10.34%; p = 0.03 and 0.28±0.46 z-score; p = 0.03).
Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.
BACKGROUND AND AIMS Sensitive outcome measures to assess the efficacy of therapeutic interventions in patients with cystic fibrosis (CF) with mild lung disease are currently lacking. Our objective was to study the ability of the lung clearance index (LCI), a measure of ventilation inhomogeneity, to detect a treatment response to hypertonic saline inhalation in paediatric patients with CF with normal spirometry. METHODS In a crossover trial, 20 patients with CF received 4 weeks of hypertonic saline (HS) and isotonic saline (IS) in a randomised sequence separated by a 4 week washout period. The primary end point was the change in the LCI due to HS versus IS. RESULTS Baseline characteristics including the LCI were not significantly different between both study periods. Four weeks of twice-daily HS inhalation significantly improved the LCI compared with IS (1.16, 95% CI 0.26 to 2.05; p=0.016), whereas other outcome measures such as spirometry and quality of life failed to reach statistical significance. Randomisation order had no significant impact on the treatment effect. CONCLUSIONS The LCI, but not spirometry was able to detect a treatment effect from HS inhalation in patients with CF with mild disease and may be a suitable tool to assess early intervention strategies in this patient population. Clinical trial number NCT00635141.
The use of alternative more sensitive measures has become a focus of research in CF. The utility of indexes of ventilation, Lung Clearance Index (LCI) and peak aerobic capacity (peak VO(2)), were studied as assessment tools in gauging response to intravenous (IV) therapy in acute pulmonary exacerbation, in comparison to the more commonly used index of forced expiratory volume in 1 sec (FEV(1)). The utility of a previously published clinical score was further explored.
Patients aged 8-18 years admitted for IV antibiotic treatment of a pulmonary exacerbation were recruited. Spirometry, plethysmography, multiple breath nitrogen washout, exercise testing, and Cystic Fibrosis Clinical Score (CFCS) were performed on admission and prior to discharge.
Twenty-eight patients were recruited, with a mean (range) age of 13.7 (8; 17) years, 16 female and 12 male. Mean (range) admission FEV(1) was 61.4 (28; 92)% predicted, or z-score -3.09 (-6.15; -0.52), FVC 83.0 (38; 120)% predicted, or z-score -1.71 (-5.66; -1.17), and Shwachman-Kulczycki 68.9 (50; 90). FEV(1) increased by 7.0% (P < 0.01) from admission to discharge. Mean (range) admission LCI, 10.10 (6.87; 14.83), decreased by 3.8% (P = 0.03). Mean (range) admission peak VO(2) (ml/kg/min), 31.2 (23.4; 45.4), increased on discharge by 6.6% (P < 0.01). Proposed clinical thresholds, based on the available variability data, highlighted the heterogeneity of response in lung function tests. Mean (range) admission CFCS, 26.5 (19; 39), decreased to 19.9 (13; 31) on discharge, a 25.2% improvement (P < 0.01). CFCS demonstrated improvement in 27 of 28 patients. Changes in peak VO(2) (r = -0.50, P = 0.02) and LCI (r = 0.48, P = 0.01) correlated with CFCS change.
In children with mild-to-moderate CF, whilst statistically significant improvement in both LCI and peak VO(2) were seen, heterogeneity of response was evident. The most consistent improvement was seen in CFCS. Correlation of LCI and peak VO(2) with change in clinical score (CFCS) was seen. The full clinical significance of these changes in LCI and peak VO(2) needs to be evaluated further with additional variability data. The CFCS may be useful in the assessment of response to treatment in CF but requires formal validation.
Inert gas washout was first described more than 60 years ago and 2 principal tests have been developed from it: the single breath and multiple breath washout (MBW) techniques. The invention of fast responding gas analysers almost 60 years ago and small computers 30 years later have facilitated breath-by-breath analysis and the development of sophisticated analysis techniques. It is now possible to detect not only the degree of pulmonary ventilation inhomogeneity, but also to gain important insight into the location of the underlying disease process. While single breath washout requires a full vital capacity effort, tidal breathing during the multiple breath test requires minimal co-operation and co-ordination, and is feasible in subjects of all ages. Available MBW normative data from parameters, such as the lung clearance index, appears to vary minimally with age, making MBW particularly useful to follow children longitudinally. Multiple breath inert gas washout has demonstrated improved sensitivity, in comparison to spirometry, in the early detection of a number of important disease processes, including cystic fibrosis. Despite this, these important techniques remain under-utilised in the clinical setting and there is a lack of commercially available devices currently available. The recent resurgence of research in this area has produced a large number of important studies and a pronounced international interest has developed in these techniques. This review article will provide an overview of the theoretical background of inert gas washout and analysis indices, review important physiological and clinical insights gained from research to date (as well as from our own experience) to illustrate its utility, and outline the challenges that lie ahead in incorporating these techniques into the mainstream clinical setting.
To apply real-time moment-ratio analysis to multibreath N2-washout curves (MBNW) from children, a new processor-controlled device was constructed. Flow and fractional N2 concentration (FN2) were each sampled by 200 Hz. An electromagnetic triple-valve system, with an instrumental dead space of 36 ml and a valve resistance of 0.3 cmH2O . l-1 . s, was connected in series with a pneumotachograph and an N2 analyzer (Ohio 720) placed next to the mouthpiece. A FORTRAN/MACRO program on a PDP 11/23 computer enabled measurement of inspiratory and expiratory flow and FN2 sampling by a 12-bit analog-to-digital converter. The fast real-time digital processing of the N2 and flow signals incorporated filtering, delay compensation, and corrections for the effects of changes in gas composition and temperature. MBNW dynamics of the lungs were studied in 17 healthy and 28 asthmatic children and in 16 patients with cystic fibrosis, evaluating the moment ratios of the washout curves as indices of the ventilation characteristics. Intrasubject variability of the moment ratios (m1/m0, m2/m0) and determination of functional residual capacity (FRC) varied between 6.3 and 14.7% (depending on which parameter is considered) and was comparatively lower than other indices previously investigated in adults. In addition, the sensitivity of the moment ratios for discriminating different stages of ventilation inhomogeneity was superior to other indices. m2/m0 is closely related to the simultaneously measured airway resistance, and the ratio between cumulative expired volume and FRC is correlated with the ratio between residual volume and total lung capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Measurement of respiratory gas composition by a mass spectrometer lags behind the measurement of gas flow. To obtain specific gas volumes (e.g., the N2 volume) by multiplication and integration of concentration and flow, one has to synchronize flow and concentration signals using the delay time (TD) of the gas analyzer. During the N2 washout, however, gas composition changes and causes alterations of TD. This leads to errors of up to 17 and 70% in the measurement of pulmonary volume and series dead space, respectively, in an ideally mixing physical model of the lung. On the basis of Poiseuille's law and exact measurements of the characteristics of the capillary it is possible to adjust the synchronization, which improves the absolute accuracy considerably.
Sensitive measures of lung function applicable to young subjects are needed to detect early cystic fibrosis (CF) lung disease. Forty children with CF aged 2 to 5 years and 37 age-matched healthy control subjects performed multiple-breath inert gas washout, plethysmography, and spirometry. Thirty children in each group successfully completed all measures, with success on first visit being between 68 and 86% for all three measures. Children with CF had significantly higher lung clearance index (mean [95% CI] difference for CF control 2.7 [1.9, 3.6], p < 0.001) and specific airway resistance (1.65 z-scores [0.96, 2.33], p < 0.001), and significantly lower forced expired volume in 0.5 seconds (-0.49 z-scores [-0.95, -0.03], p < 0.05). Abnormal lung function results were identified in 22 (73%) of 30 children with CF by multiple-breath washout, compared with 14 (47%) of 30 by plethysmography, and 4 (13%) of 30 by spirometry. Children with CF who were infected with Pseudomonas aeruginosa had significantly higher lung clearance index, but no significant difference in other lung function measures, when compared with noninfected children. Most preschool children can perform multiple-breath washout, plethysmography, and spirometry at first attempt. Multiple-breath washout detects abnormal lung function in children with CF more readily than plethysmography or spirometry.
Functional deterioration in cystic fibrosis (CF) may be reflected by increasing bronchial obstruction and, as recently shown, by ventilation inhomogeneities. This study investigated which physiological factors (airway obstruction, ventilation inhomogeneities, pulmonary hyperinflation, development of trapped gas) best express the decline in lung function, and what role specific CFTR genotypes and different types of bronchial infection may have upon this process.
Serial annual lung function tests, performed in 152 children (77 males; 75 females) with CF (age range: 6-18 y) provided data pertaining to functional residual capacity (FRCpleth, FRCMBNW), volume of trapped gas (VTG), effective specific airway resistance (sReff), lung clearance index (LCI), and forced expiratory indices (FVC, FEV1, FEF50).
All lung function parameters showed progression with age. Pulmonary hyperinflation (FRCpleth > 2SDS) was already present in 39% of patients at age 6-8 yrs, increasing to 67% at age 18 yrs. The proportion of patients with VTG > 2SDS increased from 15% to 54% during this period. Children with severe pulmonary hyperinflation and trapped gas at age 6-8 yrs showed the most pronounced disease progression over time. Age related tracking of lung function parameters commences early in life, and is significantly influenced by specific CFTR genotypes. The group with chronic P. aeruginosa infection demonstrated most rapid progression in all lung function parameters, whilst those with chronic S. aureus infection had the slowest rate of progression. LCI, measured as an index of ventilation inhomogeneities was the most sensitive discriminator between the 3 types of infection examined (p < 0.0001).
The relationships between lung function indices, CFTR genotypes and infective organisms observed in this study suggest that measurement of other lung function parameters, in addition to spirometry alone, may provide important information about disease progression in CF.
A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by high-resolution computed tomography (HRCT) in children and teenagers with CF.
A retrospective study was performed in 44 consecutive patients with CF aged 5-19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV1) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF75)) were recorded. Abnormal structure was defined as a composite HRCT score of >5%, the presence of bronchiectasis or air trapping >30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), or FEV1 or FEF75 below the predicted mean -1.96 RSD. Sensitivity/specificity assessments and correlation analyses were done.
The sensitivity to detect abnormal lung structure was 85-94% for LCI, 19-26% for FEV1 and 62-75% for FEF75. Specificity was 43-65% for LCI, 89-100% for FEV1 and 75-88% for FEF75. LCI correlated better with HRCT scores (Rs +0.85) than FEV1 (-0.62) or FEF75 (-0.66).
LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.
Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF).
LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children.
Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s > or = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%).
Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.
Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.
In cystic fibrosis (CF) lung disease, tests for ventilation inhomogeneity are sensitive but not established for clinical routine. We assessed feasibility of a new double-tracer gas single-breath washout (SBW) in school-aged children with CF and controls, and compared SBW between groups and with nitrogen multiple-breath washout (MBNW).Three SBW and MBNW were done in 118 children (66 with CF) using a side-stream ultrasonic flowmeter setup. The double-tracer gas containing 5% sulfur hexafluoride and 26.3% helium was applied during one tidal breath. Outcomes were SBW phase III slope (SIIIDTG), MBNW derived lung clearance index (LCI), and indices of acinar (Sacin) and conductive (Scond) ventilation inhomogeneity.SBW took significantly less time to perform than MBNW. SBW and MBNW were feasible in 109 (92.4%) and 98 (83.0%) children, respectively. SIIIDTG differed between children with CF and controls, mean (SD) was -456.7 (492.8) and -88.4 (129.1) mg·mol.L(-1), respectively. Abnormal SIIIDTG was present in 36 (59%) of CF children. SIIIDTG was associated with LCI (r= -0.58), Sacin (r= -0.58), but not with Scond.In CF, steeply sloping SIIIDTG potentially reflects ventilation inhomogeneity near the acinus entrance. This tidal SBW is a promising test to assess ventilation inhomogeneity in an easy and fast way.
Accurate assessment of pulmonary status in young children with cystic fibrosis (CF) requires sensitive and objective monitoring techniques.
This study aimed to evaluate the feasibility of lung clearance index (LCI) calculated from multiple breath washout (MBW), home nocturnal pulse oximetry and home nocturnal cough recording in young children with CF, and determine whether these tests can distinguish CF patients from healthy controls.
We performed a prospective cross-sectional study in 20 CF patients and 30 healthy children aged 0-4 years. MBW was performed in awake and unsedated children at the outpatient clinic using a commercially available device. Measurements of nocturnal oxygen saturation and nocturnal cough were done at home using a pulse oximeter and an audiometer.
There was a significant difference in mean LCI between healthy children and CF patients (LCI 7.1 vs. 9.3, p<0.001). Nocturnal oxygen saturation was normal in both groups and did not significantly differ between the groups. Similarly, cough showed no differences between both groups. Cough varied widely between children and between nights. Success rates for saturation and cough measurements were 90% and were similar for CF patients and healthy children. Success rate for LCI was 75% for CF patients and 50% for healthy children.
Measurements of LCI, nocturnal oxygen saturation and cough were feasible in young children; however LCI was the only variable that showed a significant difference between children with CF and healthy children.
The Lung Clearance Index (LCI) is superior to spirometry in detecting early lung disease in cystic fibrosis (CF) and correlates with structural lung changes seen on CT scans. The LCI has the potential to become a novel outcome parameter for clinical and research purposes. However longitudinal studies are required to further prove its prognostic value. Multi-center design is likely to facilitate realization of such studies.
Therefore the aim of the present study was to assess multi-center feasibility and inter-center variability of LCI measurements in healthy children and adolescents. Comparative measurements were performed in unselected patients with CF to confirm previous single-center results.
LCI measurements were performed in eight centers using the EasyOne Pro, MBW Module (ndd Medical Technologies, Zurich, Switzerland).
The overall success rate for LCI measurements was 75.5%, leaving 102/151 measurements in healthy volunteers and 139/183 measurements in patients with CF for final analysis. Age ranged between 4 and 24 years. Mean LCI (range of means among centers) was 6.3 (6.0–6.5) in healthy volunteers and thus normal. Inter-center variability of center means was 2.9%, ANOVA including Schffé procedure demonstrated no significant inter-center differences (P > 0.05). Mean LCI (range of means among centers) was 8.2 (7.4–8.9) in CF and thus abnormal.
Our study demonstrates good multi-center feasibility and low inter-center variability of the LCI in healthy volunteers when measured with the EasyOne Pro MBW module. Our data confirm published LCI data in CF. However, central coordination, quality control, regular training, and supervision during the entire study appear essential for successfully performing multi-center trials. Pediatr Pulmonol. 2012; 47:649–657.
Multiple breath washout (MBW) measurements have recently been shown to be sensitive for detection of early cystic fibrosis (CF) lung disease, with the lung clearance index (LCI) being the most common measure for ventilation inhomogeneity. The aim of this observational study was to describe the longitudinal course of LCI from time of clinical diagnosis during infancy to school-age in eleven children with CF. Elevated LCI during infancy was present in seven subjects, especially in those with later clinical diagnosis. Tracking of LCI at follow-up was evident only in the four most severe cases. We provide the first longitudinal data describing the long-term course of LCI in a small group of infants with CF. Our findings support the clinical usefulness of MBW measurements to detect and monitor early lung disease in children with CF already present shortly after clinical diagnosis.
Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S(acin)) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S(acin) and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S(acin) with normal spirometry, whereas none had airflow obstruction with normal S(acin). S(acin) and LCI were the only measures to change significantly between two visits, with both worsening. Change in S(acin) was the only parameter to correlate with change in chronic graft-versus-host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S(acin) may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.
It is widely accepted that CF lung disease starts before clinical symptoms become apparent or spirometry deteriorates. Computed chest tomography (CT) is the reference method for identifying structural changes in CF; however, radiation exposure limits its use as a monitoring tool. It has been suggested that the Lung Clearance Index (LCI) measured by Multiple Breath Washout (MBW) for assessing ventilation inhomogeneity is a more sensitive surrogate marker than spirometry allowing non-invasive monitoring of CF lung disease. The aim of this study was to prospectively investigate the diagnostic accuracy of the LCI in comparison to CT in CF patients with early lung disease and normal FEV(1) (>80% pred.). MBW and ultra-low-dose CT were performed in 34 patients (6-26 years). LCI was abnormal in 76.5% subjects. LCI and CT correlated significantly in 82.3%. LCI was related to presence and extent of structural lung changes observed on CT with a sensitivity of 88%. Diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1) was good when compared to CT. Results indicate that structural changes are unlikely if a normal LCI is measured. We speculate that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose. The LCI may be a suitable surrogate marker for monitoring progression of CF lung disease and effect of treatment in both, clinical care and research settings.
In clinical measurement comparison of a new measurement technique with an established one is often needed to see whether they agree sufficiently for the new to replace the old. Such investigations are often analysed inappropriately, notably by using correlation coefficients. The use of correlation is misleading. An alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability.
An important role for exhaled nitric oxide (NO) measurement could be in the distinction between proximal and peripheral lung contributions to inflammation, with a particular interest for the alveolar lung zone and its implication on airway function.
We aimed to isolate the acinar lung zone contribution to both inflammation and airway function to seek a relationship between them.
In 30 patients with asthma with an asthma control test score exceeding 20, indices of conductive and acinar ventilation heterogeneity (Scond, Sacin) were obtained from a multiple breath washout. NO production in the conductive airways (J'aw(NO)), alveolar NO concentration (CA(NO)), and the standard exhaled NO at 50 mL/s (FENO(50)) were obtained from exhaled NO.
Scond was consistently abnormal in all patients with stable asthma, but without any correlation to inflammation abnormality in that compartment (J'aw(NO)). Sacin was particularly abnormal in the asthma subgroup receiving >500 microg budesonide equivalent, and a correlation was found between Sacin and CA(NO) (r = 0.61; P = .015); in this subgroup, a weak association was found between Scond and J'aw(NO) or FENO(50) (r = 0.50; P = .059 for both).
The persistent functional abnormality of small conductive airways in patients with stable asthma is largely independent of inflammation as measured by exhaled NO. In the alveolar compartment, a functional correlate of alveolar NO was found in a subgroup of patients with stable asthma on moderate-to-high maintenance doses of inhaled steroids. These patients in particular could benefit from novel therapies specifically aimed at improving airway functionality at the level of the acinar entrance and beyond.
There is increasing interest in using the Multiple Breath Washout technique and the lung clearance index (LCI) for detecting early pulmonary changes, for example, in cystic fibrosis lung disease. However, there are still limited data regarding equipment specific reference ranges, repeatability and reproducibility. The aim of this prospective study was to assess within-test repeatability, short term reproducibility and long term reproducibility, and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor (EasyOne Pro, MBW Module, ndd Medical Technologies, Switzerland). Fourty-four volunteers (5.3-20.3 years) were recruited for the 1st test. Twenty-two out of 44 were measured on a 2nd test occasion after an interval of 1 hr (2nd test). Thirty-four out of 44 agreed to come back for a follow up test 6-15 months later (3rd test). Mean LCI (SD) was 6.2 (0.4), 6.3 (0.4), and 6.0 (0.4) at the 1st, 2nd, and 3rd test. The upper limit of normal was 7.0 for all subjects. Within-test repeatability was 5.1%. Short-term reproducibility (1st test vs. 2nd test) was 4.2% with a mean difference of -0.13 (95% CI -0.350; 0.087). Long-term reproducibility (1st test vs. 3rd test) was 5.1%, with a mean difference of 0.017 (95% CI -0.016; 0.348). With this low variability of the LCI for both, within and between tests, our study demonstrates reliability and robustness of equipment, protocol and analysis and the reliability of the MBW technique in general. The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases.
Advances in spirometry measurement techniques have made it possible to obtain measurements in children as young as 3 years of age; however, in practice, application remains limited by the lack of appropriate reference data for young children, which are often based on limited population-specific samples.
We aimed to build on previous models by collating existing reference data in young children (aged 3-7 yr), to produce updated prediction equations that span the preschool years and that are also linked to established reference equations for older children and adults.
The Asthma UK Collaborative Initiative was established to collate lung function data from healthy young children aged 3 to 7 years. Collaborators included researchers with access to pulmonary function test data in healthy preschool children. Spirometry centiles were created using the LMS (lambda, micro, sigma) method and extend previously published equations down to 3 years of age.
The Asthma UK centile charts for spirometry are based on the largest sample of healthy young Caucasian children aged 3-7 years (n = 3,777) from 15 centers across 11 countries and provide a continuous reference with a smooth transition into adolescence and adulthood. These equations improve existing pediatric equations by considering the between-subject variability to define a more appropriate age-dependent lower limit of normal. The collated data set reflects a variety of equipment, measurement protocols, and population characteristics and may be generalizable across different populations.
We present prediction equations for spirometry for preschool children and provide a foundation that will facilitate continued updating.
We attempted to measure the distribution of ventilation in 24 children who had cystic fibrosis (CF) and 58 control subjects (ages 3.9-6.8 years) using the multiple breath nitrogen washout (MBNW) test. Moment analysis was performed on the MBNW curve, and the first and second moment ratios were derived. Only 40 (49%) of the children were able to complete the test satisfactorily and success was related to age (P less than 0.01). Children who had CF had higher moment ratios, both first and second, than did controls (P less than 0.001); also, CF subjects who had more severe symptoms had higher moment ratios than did those who had minimal symptoms (P less than 0.005). The first moment ratio had a lower coefficient of variation than did the second (14% vs 31%) and, in 8 children who performed the test in duplicate, it also had a lower index of intrasubject variability (6.4% vs 15.1%). Both ratios were lower than those described in older children and in adults, which is consistent with the more rapid washout seen in this age group. Although moment analysis of the MBNW curve can be performed in approximately 50% of children 4 to 6-years-old, the complexity of the test, the apparatus, and the analysis and the high failure rate in children under the age of 6 are likely to restrict its use to research studies in specialized pediatric respiratory laboratories.
Measurement of lung volumes at end expiratory level and assessment of ventilation inhomogeneity is important for respiratory management in infants with lung disease. This study compared multiple breath nitrogen washout was compared with body plethysmography to measure functional residual capacity in infants and assessed ventilation inhomogeneity using mean dilution numbers and alveolar based gas dilution numbers. Measurements were performed in 23 infants with lung disorders, eleven had wheezing bronchitis, four bronchopulmonary disease, and eight cystic fibrosis. Mean age was 11.2+/-5.8 months. Functional residual capacity of nitrogen washout (29.8+/-11.4 mL x kg(-1)) was significantly (p<0.05) lower than the plethysmographically measured functional residual capacity (40.3+/-11.4 mL x kg(-1)). Tidal volumes before nitrogen washout (90.4+/-35.1 mL) were significantly larger than at the end of the washout (72.2+/-26.9 mL). Alveolar based gas dilution numbers (6.7+/-2.3) were significantly lower (p<0.001) than mean dilution numbers (10+/-5.7). Functional residual capacity determination by nitrogen washout and plethysmography in infants with lung disease showed evidence of air trapping and ventilation inhomogeneity. Ventilation inhomogeneities are best described by alveolar based dilution numbers, since rebreathing of 100% oxygen changes ventilation pattern.
Many children with cystic fibrosis (CF), receiving modern, aggressive CF care, have normal spirometry results. This study aimed to see if homogeneity of ventilation distribution is impaired early in the course of CF lung disease, and if ventilation inhomogeneity is a more frequent finding than abnormal spirometry in children benefiting from modern CF care. The study compared spirometry findings to two indices of ventilation inhomogeneity (mixing ratio (MR) and lung clearance index (LCI)) from multiple-breath inert gas washout in 43 children with CF, aged 3-18 yrs, and 28 healthy children. In total, 10/43 CF subjects (23%) had reduced forced expiratory volume in one second (FEV1) and 14/34 (41%) showed abnormal maximum expiratory flow at 25% of forced vital capacity (MEF25). In contrast, MR was abnormal in 31/43 (72%) and LCI in 27/43 (63%). MR was abnormal in 22/33 CF subjects with normal FEV1, versus 0/28 controls (p<0.001), and abnormal MR was found in 10/20 CF subjects with normal MEF25, versus 0/22 controls (p<0.001). Nine of the 10 CF subjects with reduced FEV1 and 12/14 with abnormal MEF25 showed abnormal MR. Inert gas washout discloses airway dysfunction in the majority of children with cystic fibrosis with normal lung function judged by spirometry. These findings suggest that multiple-breath inert gas washout is of greater value than spirometry in detecting early cystic fibrosis lung disease.
Patients were defined each successive month as either 'chronic' when more than 50% of the preceding 12 months were PA culture positive, 'intermittent' when < or =50% of the preceding 12 months were PA culture positive, 'free of PA', with no growth of PA for the previous 12 months, having previously been PA culture positive, or 'never infected', when PA had never been cultured.
Cross-sectional analysis of 146 children attending the Leeds Regional Cystic Fibrosis Centre was performed to assess relationship between the new definition and clinical scores and investigations. The response variable was regressed on age and sex and the residuals analysed using the Kruskal-Wallis test.
The 'chronic' group (18% of patients) had significantly worse Shwachman-Kulczycki (SK) and Northern chest X-ray scores, and % predicted FEV(1) values than the 'free' (28%) or 'never' (20%) categories (P<0.004). The 'intermittent' group (34%) had a significantly higher SK score than the 'chronic' group (P<0.0001), and a significantly lower % predicted FEV(1) value than the 'free' or 'never' groups (P<0.0003). 'Chronic' patients were significantly associated with a positive, and 'never' patients with a negative, PA antibody result (P<0.001).
The validity and importance of identifying these four subgroups is demonstrated. Previous definitions may over-estimate the prevalence of chronic infection.
Based on serial lung function measurements performed in 142 children (68 males; 74 females) with cystic fibrosis (CF), prospectively evaluated over an age range of 6 to 20 years, we attempted to determine whether the lung clearance index (LCI) as a measure of ventilation inhomogeneities could be a discriminating factor of disease progression. Annual follow-up lung function measurements featuring FRC determined by whole-body plethysmography and multibreath nitrogen washouts, effective specific airway resistance, flow-volume curves, LCI, and gas exchange characteristics were analyzed by linear mixed-model analysis and Kaplan-Meier statistics. The earliest occurring and strongest factor of progression was the LCI, followed by maximal expiratory flow (MEF(50)) and FRC determined by plethysmography (p < 0.0001). Associations between onset of chronic Pseudomonas aeruginosa infection and CF transmembrane conductance regulator (CFTR) genotype with FEV(1) (p = 0.027) and FVC (p = 0.007) were identified. The study shows that the LCI predicts earlier in life and represented much better functional progression than FEV(1). Moreover, there is no single functional predictor of progression in CF, but aside from risk factors, such as onset of chronic P. aeruginosa infection and genotype, pulmonary hyperinflation, airway obstruction, and ventilation inhomogeneities are important pathophysiologic processes that should be evaluated concomitantly as determinants of lung progression in CF.
Multiple breath inert gas washout (MBW) has been suggested as a tool for detecting early cystic fibrosis (CF) lung disease. A study was undertaken to compare the relative sensitivity of MBW and spirometry for detecting abnormal lung function in school age children with CF and to compare MBW results obtained from healthy children in the UK with those recently reported from Sweden.
Forced expiratory volume in 1 second (FEV1) and maximal expiratory flow when 25% of forced vital capacity remains to be expired (MEF25) were compared with the lung clearance index (LCI) derived from sulphur hexafluoride MBW in 22 children with CF aged 6-16 years and in 33 healthy controls.
LCI was higher in children with CF than in healthy controls (mean difference 5.1 (95% CI of difference 4.1 to 6.1) and FEV1 and MEF25 z-scores were lower (mean difference -2.3 (95% CI -2.9 to -1.7) and -1.8 (95% CI -2.4 to -1.3), respectively; p<0.001 for all). There was a significant negative correlation between LCI and FEV1 (r2 = 0.62) and MEF25 (r2 = 0.46). However, while normal (> or =-1.96 z-scores) FEV1 and MEF25 results were seen in 11 (50%) and 12 (53%) children with CF, respectively, all but one of these children had an abnormally increased LCI. LCI was repeatable in both groups (within subject CV for three measurements 6% for CF and 5% for healthy children). In healthy subjects LCI was independent of age and virtually identical in the British and Swedish children (mean difference 0.1 (95% CI -0.1 to 0.4), p = 0.38)
MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.
Over recent years, there has been renewed interest in the multiple breath wash-out (MBW) technique for assessing ventilation inhomogeneity (VI) as a measure of early lung disease in children. While currently considered the gold standard, use of mass spectrometry (MS) to measure MBW is not commercially available, thereby limiting widespread application of this technique. A mainstream ultrasonic flow sensor was marketed for MBW a few years ago, but its use was limited to infants. We have recently undertaken intensive modifications of both hardware and software for the ultrasonic system to extend its use for older children. The aim of the current in vivo study was to compare simultaneous measurements of end-tidal tracer gas concentrations and lung clearance index (LCI) from this modified ultrasonic device with those from a mass spectrometer. Paired measurements of three MBW, using 4% sulfur hexafluoride (SF(6)) as the tracer gas and the two systems in series, were obtained in nine healthy adult volunteers. End-tidal tracer gas concentrations (n = 675 paired values) demonstrated close agreement (95% CI of difference -0.23; -0.17%, r(2) = 1). FRC was slightly higher from the MS (95%CI 0.08;0.17 L), but there was no difference in LCI (95%CI -0.10; 0.3). We conclude, that this ultrasonic prototype system measures end-tidal tracer gas concentration accurately and may therefore be a valid tool for MBW beyond early childhood. This prototype system could be the basis for a commercial device allowing more widespread application of MBW in the near future.
Multiple-breath N2 washouts were performed before and after bronchodilation in 15 patients with moderately severe asthma (mean age 13 years), and in 11 patients with cystic fibrosis (CF; mean age 16 years) matched for FEV1. Eighteen healthy subjects (mean age 15 years) were studied before bronchodilation. The lung clearance index (LCI) was determined from the washout curve and gas trapping was assessed from five subsequent large breaths. Analysis of the progression of the concentration normalized phase III slopes (Sn(III)) over the washout was used to determine inhomogeneity in the conducting airways (S(cond)) and inhomogeneity close to or within the gas exchange zone (S(acin)). Before bronchodilation all washout indexes were abnormal in the CF group, and all but S(acin) in the asthma group. Two indexes were higher in CF than in asthma: LCI (11.5 (3.3) vs. 8.7 (1.3); P < 0.01), and S(acin) (0.307 (0.207) vs. 0.142 (0.071); P < 0.01), while gas trapping indexes and S(cond) (0.151 (0.071) vs. 0.127 (0.041)) did not differ significantly. After bronchodilation, all indexes improved in asthma and only S(cond) remained abnormally elevated. In CF, only a modest but statistically significant S(acin) improvement was seen and all indexes stayed abnormal. The study shows that overall ventilation inhomogeneity and particularly inhomogeneity in or close to the gas exchange zone are more pronounced in CF than in asthma matched for FEV1, while inhomogeneity in the conducting airway zone is similar. After bronchodilation, residual abnormalities of airway function are seen all through the airway tree in CF but only in the conducting airways in asthma.
Peripheral airway involvement in CF and
- Gustafsson
- Pm
Gustafsson PM. Peripheral airway involvement in CF and
The effect of humidity on the performance of respiratory nitro-gen analysers [abstract]
- Robinson Pd M Turner
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- M Strö
- Gustafsson
- Pm
Robinson PD, Turner M, King GG, Strö M, Gustafsson PM. The effect of humidity on the performance of respiratory nitro-gen analysers [abstract]. Eur Respir J 2010;36:s843.
statement: pulmonary function testing in preschool children
- N Beydon
- Sd Davis
- E Lombardi
- Jl Allen
- Hg Arets
- P Aurora
- H Bisgaard
- Gm Davis
- Fm Ducharme
- H Eigen
- M Gappa
- C Gaultier
- Pm Gustafsson
- Gl Hall
- Z Hantos
- Mj Healy
- Mh Jones
- B Klug
- Lodrup Carlsen
- Kc Mckenzie
- Sa Marchal
- F Mayer
- Oh Merkus
- Pj Morris
- Mg Oostveen
- E Pillow
- Jj Seddon
- Pc Silverman
- M Sly
- Pd Stocks
- J Tepper
- Rs Vilozni
- D Wilson
Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora
P, Bisgaard H, Davis GM, Ducharme FM, Eigen H, Gappa M,
Gaultier C, Gustafsson PM, Hall GL, Hantos Z, Healy MJ,
Jones MH, Klug B, Lodrup Carlsen KC, McKenzie SA, Marchal
F, Mayer OH, Merkus PJ, Morris MG, Oostveen E, Pillow JJ,
Seddon PC, Silverman M, Sly PD, Stocks J, Tepper RS, Vilozni
D, Wilson NM. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in
preschool children. Am J Respir Crit Care Med 2007;175:1304–
1345.
Statistical methods for assessing agreement between two methods of clinical measurement
- Bland JM
- Altman DG
European Respiratory Society statement: pulmonary function testing in preschool children
- N Beydon
- S D Davis
- E Lombardi
- J L Allen
- H G Arets
- Aurora P Bisgaard
- H Davis
- G M Ducharme
- F M Eigen
- H Gappa
- M Gaultier
- C Gustafsson
- P M Hall
- G L Hantos
- Z Healy
- M J Jones
- M H Klug
- Lodrup Carlsen
- K C Mckenzie
- S A Marchal
- F Mayer
- O H Merkus
- P J Morris
- M G Oostveen
- E Pillow
- J J Seddon
- P C Silverman
- M Sly
- P D Stocks
- J Tepper
- R S Vilozni
- D Wilson
Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora
P, Bisgaard H, Davis GM, Ducharme FM, Eigen H, Gappa M,
Gaultier C, Gustafsson PM, Hall GL, Hantos Z, Healy MJ,
Jones MH, Klug B, Lodrup Carlsen KC, McKenzie SA, Marchal
F, Mayer OH, Merkus PJ, Morris MG, Oostveen E, Pillow JJ,
Seddon PC, Silverman M, Sly PD, Stocks J, Tepper RS, Vilozni
D, Wilson NM. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in
preschool children. Am J Respir Crit Care Med 2007;175:1304-1345.
The effect of humidity on the performance of respiratory nitrogen analysers
- P D Robinson
- M Turner
- G G King
- M Ström
- P M Gustafsson
Robinson PD, Turner M, King GG, Ström M, Gustafsson PM.
The effect of humidity on the performance of respiratory nitrogen analysers [abstract].
The effect of humidity on the performance of respiratory nitrogen analysers [abstract]
- Robinson PD