H.G.M. Arets

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Forced expiratory manoeuvres in children: do they meet ATS and ERS criteria for spirometry?

The aim of this study was to evaluate the applicability of American Thoracic Society and European Respiratory Society criteria for spirometry in children. Maximal expiratory flow/volume (MEFV) measurements from 446 school-age children, experienced in performing MEFV manoeuvres, were studied and acceptability (start-of-test (backward extrapolated volume as a percentage of forced vital capacity (FVC) ([Vbc%FVC) or as an absolute value (Vbe), end-of-test (forced expiratory time (FET)) and reproducibility criteria (absolute and percentage difference between best and second-best FVC and forced expiratory volume in one second (FEV1) (deltaFVC, deltaFVC %, deltaFEV1 and deltaFEV1 %)) were applied to these manoeuvres. The Vbe%FVC criterion was met by 91.5%, the Vbe <0.15 L criterion by 94.8% and the Vbe <0.10 L by 60.1% of children. Vbe <0.15 L appeared to be a more useful parameter than Vbe%FVC. The FET criterion was met by only 15.3% of children. deltaFVC <0.2 L and deltaFEV1 <0.2 L were met by 97.1% and 98.4%, and deltaFVC <0.1 L and deltaFEV1 <0.1 L by 79.8% and 84.3% of the children, respectively. These criteria appeared to be less useful compared to percentage criteria (deltaFVC % and deltaFEV1 %). Even experienced children did not meet all international criteria for spirometry. However, most of their MEFV curves are useful for interpretation. Based on the performance of these children, a re-evaluation of criteria for maximal expiratory flow/volume measurements in children is proposed.

Measurements of interrupter resistance: reference values for children 3-13 yrs of age

The interrupter technique is a convenient and sensitive technique for studying airway function in subjects who cannot actively participate in (forced) ventilatory function tests. Reference values for preschool children exist but are lacking for children >7 yrs. Reference values were obtained for expiratory interrupter resistance (Rint,e) in 208 healthy Dutch Caucasian children 3–13 yrs of age. A curvilinear relationship between Rint,e and height was observed, similar to published airways resistance data measured by plethysmography. No significant differences in cross-sectional trend or level of Rint,e were observed according to sex. It was found that Z-scores could be used to express individual Rint,e values and to describe intra- and interindividual differences based on the reference equation: 10logRint,e=0.645–0.00668×standing height (cm) kPa·L−1·s−1 and residual SD (0.093 kPa·L−1·s−1). Expiratory interrupter resistance provides a tool for clinical and epidemiological assessment of airway function in a large age range.

Upper and lower airway cultures in children with cystic fibrosis: do not neglect the upper airways.

BACKGROUND Airways of cystic fibrosis (CF) patients are colonised with bacteria early in life. We aimed to analyse differences between results of simultaneously taken upper airway (UAW) and lower airway (LAW) cultures, to describe clinical characteristics of patients with positive versus negative cultures and to follow up the patients with P. aeruginosa positive UAW cultures. METHODS Bacteriological and clinical data from 157 children were collected during annual check up. The number of positive UAW and LAW cultures and correspondence between these results and clinical characteristics were analysed. RESULTS Positive LAW and UAW cultures were found in 79.6% and 43.9% of patients respectively (p<0.001). Patients with positive LAW cultures were significantly older (11.9 vs. 9.8years, p<0.05) and had more LAW symptoms (73.6% vs. 46.7%, p<0.05), especially when P. aeruginosa was found. Patients with positive UAW cultures (especially S. aureus) had more nasal discharge (50.7% vs. 25.0%, p<0.001). In 65% of patients with positive UAW and negative LAW culture for P. aeruginosa the next LAW became P. aeruginosa positive. CONCLUSION UAW cultures and LAW cultures differ in children with CF and there are differences in clinical characteristics between patients with positive versus negative culture results. P. aeruginosa positive UAW cultures appeared to precede positive LAW cultures in a substantial part of patients, suggesting some kind of cross-infection between the UAW and LAW.

Statement on Exercise Testing in Cystic Fibrosis.

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.

Chronic infection and inflammation affect exercise capacity in cystic fibrosis

Pulmonary function and nutritional status are important determinants of exercise capacity in patients with cystic fibrosis (CF). Studies investigating the effects of determinants, such as genotype or infection and inflammation, are scarce and have never been analysed in a multivariate longitudinal model. A prospective longitudinal cohort study was performed to evaluate whether genotype, chronic inflammation and infection were associated with changes in exercise capacity. Furthermore, we investigated whether exercise capacity can predict clinical outcome. 504 exercise tests of 149 adolescents with CF were evaluated. Maximal oxygen uptake corrected for body mass % predicted declined 20% during adolescence, and was associated with immunoglobulin (Ig)G levels and chronic Pseudomonas aeruginosa infection. A lower exercise capacity was associated with a higher mortality, steeper decline in pulmonary function and greater increase in IgG levels. Since a decline in exercise capacity during adolescence was negatively associated with IgG levels and chronic P. aeruginosa infection, these data emphasise the importance of prevention and treatment of chronic inflammation and infections in patients with CF. Furthermore, a lower exercise capacity was associated with a higher mortality rate, steeper decline in pulmonary function and higher increase in IgG levels with increasing age in adolescents with CF. This stresses the value of regular exercise testing for assessing prognosis in adolescents with CF.

Gastric Acid Inhibition for Fat Malabsorption or Gastroesophageal Reflux Disease in Cystic Fibrosis: Longitudinal Effect on Bacterial Colonization and Pulmonary Function

OBJECTIVES To investigate bacterial colonization and pulmonary function longitudinally in patients with cystic fibrosis (CF) receiving drugs for gastric acid (GA) inhibition for fat malabsorption or for gastroesophageal reflux disease (GERD). STUDY DESIGN A retrospective cohort study of 218 pediatric patients with CF was performed. Multilevel modeling was used to perform longitudinal analysis of forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), maximum expiratory flow at 50% of FVC (MEF(50)), and maximal mid-expiratory flow between 25% and 75% of FVC (MMEF(25-75)). Cox regression was used to calculate Pseudomonas aeruginosa- and Staphylococcus aureus-free survival. RESULTS Patients with CF and GA inhibition had a significantly smaller yearly decline of MEF(50) and MMEF(25-75) compared with control subjects. Other pulmonary function parameters and P aeruginosa or S aureus acquisition or colonization were not different from that of control subjects. GERD was associated with a significantly reduced pulmonary function (FEV(1) and FVC) and an earlier acquisition of P aeruginosa and S aureus. CONCLUSIONS GA inhibition did not affect pulmonary function or bacterial acquisition and therefore is not contraindicated in patients with CF. GA inhibition might improve pulmonary function with time, because the decline of MEF(50) and MMEF(25-75) was less pronounced. GERD was associated with a reduced pulmonary function and an earlier acquisition of P aeruginosa and S aureus. Therefore the diagnosis and treatment of GERD should be aggressively pursued in patients with CF.

Optimal Complement-Mediated Phagocytosis of Pseudomonas aeruginosa by Monocytes Is Cystic Fibrosis Transmembrane Conductance Regulator–Dependent

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is characterized by chronic pulmonary infections. The mechanisms underlying chronic infection and inflammation remain incompletely understood. Mutant CFTR in nonepithelial tissues such as immune cells has been suggested to contribute to infection, inflammation, and the resultant lung disease. However, much controversy still exists regarding the intrinsic role of CFTR in immune cells, especially phagocytes. Therefore, we investigated CFTR expression and function in neutrophils and monocytes isolated from human peripheral blood. CFTR function was assessed by comparing non-CF and CF cells, before and after the chemical inhibition of CFTR. We found CFTR protein expression in monocytes, but this expression was limited or undetectable in neutrophils. Furthermore, the phagocytosis and intracellular killing of Pseudomonas aeruginosa was reduced in CF monocytes, and impaired phagocyte effector mechanisms were phenocopied in non-CF monocytes upon the pharmacological inhibition of CFTR. Reduced phagocytosis in CF monocytes relied on the complement-dependent opsonization of Pseudomonas aeruginosa, and was also observed in the context of latex particles labeled with purified C3b. In mechanistic terms, we observed that CFTR function in monocytes is required for the optimal expression of CD11b. We observed no role for CFTR in neutrophil-mediated phagocytosis. These data support an intrinsic role for CFTR in monocytes, and suggest that CFTR-dependent alterations in complement-mediated interactions between Pseudomonas aeruginosa and monocytes may contribute to enhanced susceptibility to infection in patients with CF.

Survey of clinical infant lung function testing practices

Data supporting the clinical use of infant lung function (ILF) tests are limited making the interpretation of clinical ILF measures difficult.

Prediction of Mortality in Adolescents with Cystic Fibrosis

INTRODUCTION Lung function, nutritional status, and parameters of exercise capacity are known predictors of mortality in patients with cystic fibrosis (CF). The aim of the current study was to use these important parameters to develop a multivariate model to predict mortality in adolescent patients with CF. METHODS A total of 127 adolescents with CF (57 girls) with a mean age of 12.7 ± 0.9 yr and a mean percentage of predicted forced expired volume in 1 s (FEV1% predicted) of 77.7% ± 15.6% were included. Cardiopulmonary exercise testing-derived parameters, nutritional status, and resting lung functions were dichotomized according to the criterion value determined using receiver operating characteristic curves. Body mass index (BMI), FEV1%predicted, predicted peak oxygen uptake corrected for body weight (VO2 peak/kg%predicted), peak minute ventilation (VE peak), peak VE/VO2, peak VE/VCO2, and breathing reserve were included in a multivariate model. The Cox proportional hazards model was used to determine the combination of parameters that best predicted mortality and/or lung transplantation. RESULTS The mean duration of follow-up was 7.5 ± 2.7 yr, during which, nine of the 127 patients (7.1%) died and six (4.7%) underwent lung transplantation. Mortality in this population was best predicted by the model that included FEV1%predicted (hazard ratio, 17.13; 95% confidence interval (CI), 3.76-78.06), peak VE/VO2 (hazard ratio, 5.92; 95% CI, 1.27-27.63), and BMI (hazard ratio, 5.54; 95% CI, 1.82-16.83). CONCLUSIONS The currently developed model consisting of BMI, FEV1%predicted, and VE/VO2 is a strong predictor of mortality rate in adolescents with CF. This prediction equation may be useful in clinical practice to detect patients with a high risk of mortality and to provide them with additional therapy earlier.