[Show abstract][Hide abstract] ABSTRACT: This statement summarizes the information available on specific exercise test protocols and outcome parameters used in patients with cystic fibrosis (CF) and provides expert consensus recommendations for protocol and performance of exercise tests and basic interpretation of results for clinicians. The conclusions were reached employing consensus meetings and a wide-band Delphi process. Although data on utility are currently limited, standardized exercise testing provides detailed information on physiological health, allows screening for exercise-related adverse reactions and enables exercise counselling. The Godfrey Cycle Ergometer Protocol with monitoring of oxygen saturation and ventilatory gas exchange is recommended for exercise testing in people 10 years and older. Cycle ergometry only with pulse oximetry using the Godfrey protocol or treadmill exercise with pulse oximetry - preferably with measurement of gas exchange - are second best options. Peak oxygen uptake, if assessed, and maximal work rate should be reported as the primary measure of exercise capacity. The final statement was reviewed by the European Cystic Fibrosis society and revised based on the comments received. The document was endorsed by the European Respiratory Society.
[Show abstract][Hide abstract] ABSTRACT: The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.
Annals of the American Thoracic Society 06/2015; 12(6):932-939. DOI:10.1513/AnnalsATS.201501-021FR
[Show abstract][Hide abstract] ABSTRACT: Background In patients with cystic fibrosis (CF), interpretation of cross-sectional FEV1 data is greatly influenced by choice of spirometry reference equation, particularly during childhood (Stanojevic; J Cyst Fibros 2014). We hypothesised that availability of the Global Lung Function Initiative (GLI) spirometry reference equations (Quanjer; ERJ 2012) will also affect the apparent rate of decline in lung function over time, thereby potentially altering our understanding of disease progression in CF.
Methods Data were extracted from two patient registries: the UK CF Registry (n = 6043 subjects; 20,013 test occasions over a period of 5 years) and the Toronto CF database (n = 1023 subjects; 27,868 test occasions over a period of 23 years). Spirometric outcomes were interpreted using%predicted FEV1 calculated from GLI, Knudson (as currently used by the UK CF Registry), and Wang-Hankinson (as used by the US CF Foundation) reference equations. Patients >30 yrs or with FEV1 > 130% predicted were excluded. We used a non-linear mixed effects model to describe the average change in FEV1 with age. To illustrate the importance of reference equation in evaluating risk factors, FEV1 decline according to patient gender was also explored.
Results The pattern of lung function decline at the population level differed according to selected equation (Figure). Average rate of decline was steeper with Knudson or Wang-Hankinson than GLI. Importantly, GLI equations showed a steady decline in FEV1 starting at 6 yrs, whereas the other equations suggest greater decline during adolescence. Similar patterns were observed in both UK and Toronto populations. When analysed according to gender, the rate of lung function decline was steeper in females during early adolescence compared with males where the decline was steady.
Conclusions In both datasets, Knudson and Wang-Hankinson reference equations suggest relative preservation of spirometry in childhood followed by rapid decline in adolescence. However using the more robust GLI equations, steady decline throughout childhood with a less dramatic acceleration during adolescence is seen, with differences in pattern of change over time according to patient gender. Accurate identification of critical periods of lung function decline offers novel opportunities to target care.
Funded by the UK CF Trust.
[Show abstract][Hide abstract] ABSTRACT: Background. Mycobacterium abscessus has emerged as a major pathogen in cystic fibrosis (CF) patients and has been associated with poor clinical outcomes, particularly following lung transplant. We investigated the acquisition of this bacterium in a cohort of pediatric CF patients.
Methods. Demographic and patient location data were used to uncover epidemiological links between patients with genetically related strains of M. abscessus that had been previously typed by variable-number tandem repeat profiling. Whole-genome sequencing was applied to 27 M. abscessus isolates from the 20 patients in this cohort to provide definitive data on the genetic relatedness of strains.
Results. Whole-genome sequencing data demonstrated that M. abscessus isolates from 16 patients were unrelated, differing by at least 34 single-nucleotide polymorphisms (SNPs) from any other isolate, suggesting that independent acquisition events have occurred. Only 2 clusters of very closely related (<25 SNPs) isolates from different patients were seen. The first cluster contained 8 isolates, differing by a maximum of 17 SNPs, from a sibling pair who had intense exposure to each other both inside and outside the hospital. The second cluster contained 3 isolates, differing by a maximum of 24 SNPs, from 2 individuals with no apparent epidemiological links.
Conclusions. We have not demonstrated cross-transmission of M. abscessus within our hospital, except between 1 sibling pair. Alternative routes of acquisition of M. abscessus infection, in particular the environment, require further investigation.
[Show abstract][Hide abstract] ABSTRACT: Background Multiple breath inert-gas washout (MBW) using sulphur hexafluoride (SF6) measured by mass spectrometry (MS), is sensitive to early lung disease in children with Cystic Fibrosis (CF)1 but is not widely available. To increase the accessibility of MBW, commercial devices have been adapted using nitrogenwashout (N2-MBW). Our aim was to assess the feasibility of two commercial N2-MBW devices as supplied by the manufacturers compared to a custom-built MS system in school-aged children.
Methods Patients with CF and controls performed MBW on three devices; the Exhalyzer®D (ECO MEDICS AG); the EasyOne Pro®LAB (ndd Medizintechnik AG) and the MS system (AMIS 2000, Innovision ApS) on the same test occasion (order randomised). Attempts were made to obtain 3 technically acceptable runs/device (maximum 8 attempts on each).
During testing children watched a DVD and were encouraged to breathe normally. Data were analysed using the ‘clinical application’ setting for both commercial devices, and customised software for the MS. Quality control was in accordance with the ATS/ERS consensus statement1 and manufacturers’ guidelines.
Results 14 control (mean[range]age: 15.0[12.5–16.7]yrs) and 18 children with CF (13.5[7.8–17.4]yrs) were assessed. The median (range) number of runs attempted were: MS 3(3–8), Exhalyzer®D 4(3–6), EasyOne Pro®LAB 4(3–8). Average calibration time was shorter for EasyOne Pro®LAB (5 min) than either MS (11 mins) or Exhalyzer®D (12 min). Total test duration was similar between devices and dependent on disease severity.
3 acceptable MBW runs were achieved in all children using the MS, 75% with the EasyOne Pro®LAB, and 47% on the Exhalyzer®D system (see Table). Reasons for failure with Exhalyzer®D were usually due to technical/equipment problems, whereas for the EasyOne Pro®LAB these were generally associated with marked changes of breathing pattern at commencement of washout, leading to exclusion of one or more runs.
Discussion Despite use in an experienced MBW centre, our initial attempts to implement commercial MBW devices according to manufacturers’ guidelines resulted in a relatively low success rate in schoolchildren when compared to MS. Subsequent feedback to manufacturers has led to further adaptations which should improve feasibility in future, although this has yet to be assessed in very young children.
[Show abstract][Hide abstract] ABSTRACT: Assessment of ventilation inhomogeneity using the multiple breath washout (MBW) technique has been shown to be more sensitive than spirometry in detecting early cystic fibrosis lung disease throughout childhood. The current “gold standard” interface for school age children and adults is a mouthpiece. Although masks are better tolerated by infants and younger children, their use increases equipment deadspace-which could influence measured values and hence interpretation of results. The aim of this study was to examine the effect of using a mask vs mouthpiece on values of functional residual capacity (FRC) and the lung clearance index (LCI) derived from MBW.
Method Comparisons were performed in healthy adults. The study design incorporated repeated measures as well as interface comparison. The mask was selected to mimic measurement conditions in infants, the deadspace of 85 mL being approximately 1–2 ml/kg in adults. Mouthpiece (MP) deadspace was ~5 ml. Subjects were randomly allocated to group A (Mask-Mouthpiece-Mouthpiece) or group B (Mouthpiece-Mouthpiece-Mask) protocols. Each subject performed a total of 9 MBW runs, in 3 sets, each consisting of 3 runs, with a 5-minute break between each set. MBW was performed using a mass spectrometer as described previously (Aurora 2005 AJRCCM). Paired t-tests with 95% limits of agreement were used to establish repeatability (MP1 vs. MP2) and any differences between Mask vs. Mouthpiece. This study was approved by the local research ethics committee and written consent obtained from subjects.
Results Technically satisfactory comparative data were obtained on 15 occasions in 14 adults (36% males; age: 22–56 years). Respiratory rate and tidal volume were similar using either approach. Repeatability: Both FRC and LCI were repeatable using the mouthpiece [(Mean (95% CI) diff: FRC: 0.012L (-0.05;0.07); LCI: -0.1(-0.3; 0.1)]; Figure 1A and B. Mask vs. Mouthpiece: FRC and LCI were both significantly higher when assessments were made using a mask compared with a mouthpiece: FRC: 0.101L (0; 0.202); LCI: 0.4 (0.2;0.7); Figure 1C and D.
Conclusion The increase in LCI when using a facemask exceeded normal within test variability in adults and could influence interpretation of results especially if different patient interfaces are used when collecting data in younger children.
[Show abstract][Hide abstract] ABSTRACT: Background: Lung clearance index (LCI) measured by multiple breath washout (MBW) is a sensitive indicator of early lung disease in Cystic Fibrosis (CF).1 MBW using sulphur hexafluoride (SF6) and mass spectrometry (MS) is currently the gold standard, but equipment is limited to a few centres. Although commercial devices based on SF6 have been developed, use of SF6 is expensive and restricted in some countries. Commercial devices using nitrogen (N2), which is cheaper and widely available, have been developed recently to increase accessibility of this test in research and clinical practice but have yet to be validated in children. The aim of this study was to compare values of LCI and Functional Residual Capacity (FRC) in children using the N2-MBW EasyOne Pro® LAB system (ndd Medical Technologies) and the MS (AMIS 2000, Innovision ApS).
Methods: School-age children with CF and healthy controls completed MBW in triplicate on both the EasyOne Pro® and MS in random order on the same occasion. Within-subject agreement between devices for LCI and FRC was assessed by Bland-Altman analysis.
Results: Of the 50 children recruited, all completed testing using MS, while 5 failed quality control on the EasyOne Pro® LAB. Paired results from both devices were obtained in 26 children with CF (mean age [range]) (13.3y[7.8y-17.4y]) and 19 controls (14.8y [12.5y-16.7y]). LCI was significantly higher in those with CF when using both devices (mean difference[95% CI], CF-controls): 2.47[1.4;3.5] for the MS-SF6 and 2.20[1.2–3.2] for N2-MBW.
There were no significant group differences between devices for either LCI (mean difference[95% CI]) -0.14[-0.45;0.16] or FRC -0.15L[-0.2;-0.08]. Within-subject variability was proportional to mean values (see Figure) and ranged from 0.4–15.7% for LCI and 0.0–19.6% for FRC.
Conclusion: Despite some previous reports that N2-washout results in higher LCI values than MS-SF6 washout, on average, we found similar values in both healthy school-age children and those with CF. Further work is required to examine causes of within-subject variability and assess validity and sensitivity over a wider age range, including preschool children, before commercial N2-MBW devices can be confidently used in multi-centre trials.
Reference: Aurora et al. Am J Respir Crit Care Med. 2011;183:752–8
[Show abstract][Hide abstract] ABSTRACT: There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation.
Erratum to “Practical Guidelines: Lung Transplantation in Patients with Cystic Fibrosis”
Pulmonary Medicine 05/2014; 2014(10):621342. DOI:10.1155/2014/621342
[Show abstract][Hide abstract] ABSTRACT: The Quanjer et al. Global Lung Function Initiative (GLI)-2012 multi-ethnic all-age reference equations for spirometry are endorsed by all major respiratory societies and are the new gold standard. Before the GLI equations are implemented for use in CF patients, the impact of changing equations from those currently used needs to be better understood.
Annual review data submitted to the UK CF Trust Registry between 2007 and 2011 were used to calculate %predicted FEV1, FVC and FEV1/FVC using three widely used reference equations (Wang-Hankinson and Knudson) and the new GLI-2012 equations.
Overall, Knudson and Wang equations overestimated %predicted values in paediatric patients, such that a greater proportion of patients had lung function values in the normal range. Within individual patients, the impact of switching equations varied greatly depending on the patients' age, and which equations were used.
A unified approach to interpreting spirometric lung function measurements would help facilitate more appropriate comparison both within and between centres and countries. Interpretation of longitudinal measurements using a continuous reference equation across all-ages, like the GLI, may further improve our understanding of CF lung disease.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 12/2013; 12(3). DOI:10.1016/j.jcf.2013.11.006 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants.
To assess changes in pulmonary function during the first year of life in CF NBS infants.
Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV0.5) were measured at 3 months and 1 year of age.
Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year.
This is the first study reporting improvements in FEV0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.