Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Associations of extracurricular physical activity patterns and body composition components in a multi-ethnic population of UK children (the Size and Lung Function in Children study): a multilevel modelling analysis.

BACKGROUND: Body Mass Index (BMI) is a common outcome when assessing associations between childhood overweight and obesity and physical activity patterns. However, the fat and fat-free components of BMI, measured by the Fat Mass Index (FMI) and Fat-Free Mass Index (FFMI), may show contrasting associations with physical activity, while ethnic groups may vary in both physical activity patterns and body composition. Body composition must therefore be evaluated when assessing the associations between childhood overweight and obesity and physical activity in multi-ethnic populations. METHODS: This cross-sectional study investigated associations of BMI, FMI and FFMI z-scores with extracurricular physical activity for 2171 London primary schoolchildren (aged 5-11 years) of black, South Asian and white/other ethnicity. Multilevel mixed-effects ordered logistic modelling was used, adjusting for age, sex and family and neighbourhood socioeconomic status as potential confounders. RESULTS: Controlling for ethnicity and individual, family and neighbourhood socioeconomic confounders, actively commuting children had significantly lower Odds Ratios for being in high BMI (Odds Ratio (OR) = 0.678; 95 % Confidence Interval (CI) = 0.531 - 0.865; p - value = 0.002) and FMI z-score groups (OR = 0.679; 95 % CI = 0.499 - 0.922; p = 0.013), but not FFMI z-score groups, than passive commuters. Children doing sports less than once a week had lower Odds Ratios for being in high BMI (OR = 0.435; 95 % CI = 0.236 - 0.802; p = 0.008) and FFMI (OR = 0.455; 95 % CI = 0.214 - 0.969; p = .041) z-score categories compared to daily active children. Differences in FMI between groups did not reach the significance threshold. A trend towards statistical significance was obtained whereby children's complete inactivity was associated with higher odds for being in higher BMI (OR = 2.222 : 95 % CI = 0.977 - 5.052; p = .057) and FMI z-score groups (OR = 2.485 : 95 % CI = 0.961 - 6.429; p = .060). FFMI z-scores did not show a similar trend with complete inactivity. CONCLUSIONS: Active commuting was objectively associated with lower adiposity, while more frequent extracurricular sports participation was correlated with greater fat-free mass accretion. These relationships were independent of ethnicity and individual, family or neighbourhood socioeconomic confounding factors.

Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient.

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration.

UNLABELLED: The raised volume rapid thoracoabdominal compression (RVRTC) technique is commonly used to obtain full forced expiratory manoeuvres from infants, but reference equations derived from 'in-house' equipment have been shown to be inappropriate for current commercially available devices. AIM: To explore the impact of equipment differences on RVRTC outcomes, derive robust equipment-specific RVRTC reference ranges and investigate their potential clinical impact on data interpretation. METHOD: RVRTC data from healthy subjects using Jaeger BabyBody or the 'Respiratory Analysis Software Program, RASP' systems were collated from four centres internationally. Data were excluded if gestational age <37 weeks or birth weight <2.5 kg. Reference equations for RVRTC outcomes were constructed using the LMS (lambda-mu-sigma) method, and compared with published equations using data from newborn screened infants with cystic fibrosis (CF). RESULTS: RVRTC data from 429 healthy infants (50.3% boys; 88% white infants) on 639 occasions aged 4-118 weeks were available. When plotted against length, flows were significantly higher with RASP than Jaeger, requiring construction of separate equipment-specific regression equations. When comparing results derived from the new equations with those from widely used published equations based on different equipments, discrepancies in forced expiratory volumes and flows of up to 2.5 z-scores were observed, the magnitude of which increased with age. According to published equations, 25% of infants with CF fell below the 95% limits of normal for FEV0.5, compared with only 10% when using the new equations. CONCLUSIONS: Use of equipment-specific prediction equations for RVRTC outcomes will enhance interpretation of infant lung function results; particularly during longitudinal follow-up.

Natural variability of lung function in young healthy school children.

Knowledge about long-term variability of lung function in healthy children is essential when monitoring and treating those with respiratory disease over time. The aim of this study was to define the natural variability in spirometry in young children after an interval of 12 months.The Size and Lung function In Children study was a prospective study designed to assess spirometry and body size, shape and composition in a multi-ethnic population of London school children. 14 schools with a wide range of socioeconomic circumstances were recruited. Spirometric and anthropometric assessments and parental questionnaires pertaining to respiratory symptoms, previous medical history, pubertal status and socioeconomic circumstances were completed at baseline and ∼1 year later.Technically acceptable spirometry data on two occasions ∼1 year apart (range 9-16 months) were available in 758 children (39% boys, mean±sd age 8.1±1.6 years), 593 of whom were classified as "healthy". Mean±sd within-subject between-test variability was 0.05±0.6 z-scores, with 95% of all the children achieving a between-test variability within ±1.2 z-scores (equating to ∼13% predicted).Natural variations of up to 1.2 z-scores occur in healthy children over ∼1 year. These must be considered when interpreting results from annual reviews in those with lung disease who are otherwise stable, if unnecessary further investigations or changes in treatment are to be avoided.

Disparities in pulmonary function in healthy children across the Indian urban-rural continuum.

RATIONALE: Marked socioeconomic health-care disparities are recognized in India, but lung health inequalities between urban and rural children have not been studied. OBJECTIVES: We investigated whether differences exist in spirometric pulmonary function in healthy children across the Indian urban-rural continuum and compared results with those from Indian children living in the UK. METHODS: Indian children aged 5 to 12 years were recruited from Indian urban, semiurban, and rural schools, and as part of the Size and Lung Function in Children study, London. Anthropometric and spirometric assessments were undertaken. MEASUREMENTS AND MAIN RESULTS: Acceptable spirometric data were obtained from 728 (58% boys) children in India and 311 (50% boys) UK-Indian children. As an entire group, the India-resident children had significantly lower z FEV1 and z FVC than UK-Indian children (P < 0.0005), when expressed using Global Lung Function Initiative-2012 equations. However, when India-resident children were categorized according to residence, there were no differences in z FEV1 and z FVC between Indian-urban and UK-Indian children. There were, however, significant reductions of ∼ 0.5 z scores and 0.9 z scores in both FEV1 and FVC (with no difference in FEV1/FVC) in Indian-semiurban and Indian-rural children, respectively, when compared with Indian-urban children (P < 0.0005). z Body mass index, socioeconomic circumstances, tobacco, and biomass exposure were individually significantly associated with z FEV1 and z FVC (P < 0.0005). CONCLUSIONS: The presence of an urban-rural continuum of lung function within a specific ethnic group emphasizes the impact of environmental factors on lung growth in emerging nations such as India, which must be taken into account when developing ethnic-specific reference values or designing studies to optimize lung health.

How "healthy" should children be when selecting reference samples for spirometry?

How "healthy" do children need to be when selecting reference samples for spirometry? Anthropometry and spirometry were measured in an unselected, multi-ethnic population of school children aged 5-11 years in London, UK, with follow-up assessments 12 months later. Parents provided information on children's birth data and health status. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were adjusted for sex, age, height and ethnicity using the 2012 Global Lungs Initiative equations, and the effects of potential exclusion criteria on the z-score distributions were examined. After exclusions for current and chronic lung disease, acceptable data were available for 1901 children on 2767 occasions. Healthy children were defined as those without prior asthma or hospitalisation for respiratory problems, who were born at full-term with a birthweight ≥2.5 kg and who were asymptomatic at testing. Mean±sd z-scores for FEV1 and FVC approximated 0±1, indicating the 2012 Global Lungs Initiative equations were appropriate for this healthy population. However, if children born preterm or with low birthweight, children with prior asthma or children mildly symptomatic at testing were included in the reference, overall results were similar to those for healthy children, while increasing the sample size by 25%. With the exception of clear-cut factors, such as current and chronic respiratory disease, paediatric reference samples for spirometry can be relatively inclusive and hence more generalisable to the target population.

Lung function in children in relation to ethnicity, physique and socioeconomic factors.

Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors?Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1 year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure.Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2-11.8) years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1 s was 1.32, 0.89 and 0.51 z-score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances.Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results.

Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants.

RATIONALE: 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. OBJECTIVE: To assess changes in pulmonary function during the first year of life in CF NBS infants. METHODS: 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. MAIN RESULTS: 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. CONCLUSIONS: 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.

How to avoid misinterpreting lung function tests in children: a few practical tips.

Assessments of pulmonary function play an integral part in the clinical management of school age children as well as providing objective outcome measures in clinical and epidemiological research studies. Pulmonary function tests (PFTs) can also be undertaken in sleeping infants and in awake young children from 3 years of age. However, the clinical utility of such assessments, which are generally confined to specialist centres, has yet to be established. Whether requesting or undertaking paediatric PFTs, or simply reading about how these tests have been applied in research studies, it is essential to question whether results have been interpreted in a meaningful way. This review summarises some of the issues that need to be considered, including: why the tests are being performed; which tests are most likely to detect the suspected pathophysiology; how often such tests should be repeated; whether results are likely to be reliable (in terms of data quality, repeatability and the availability of suitable reference equations with which to distinguish the effects of disease from those of growth and development), and whether the selected tests are likely to be feasible in the individual child or study group under investigation.

Age and height dependence of lung clearance index and functional residual capacity.

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.

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.

Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening.

BACKGROUND: Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. HYPOTHESIS: With early diagnosis and commencement of standardised treatment, lung function at ∼3 months of age is normal in NBS infants with CF. METHODS: Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ∼3 months. RESULTS: Compared with controls, and after adjustment for body size and age, LCI, FRC(MBW) and FRC(pleth) were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV(0.5)) and flows (FEF(25-75)) were significantly lower (-0.9 (-1.3 to -0.6), p<0.001 and -0.7 (-1.1 to -0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV(0.5) (below -1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV(0.5), using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC(pleth) >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF(25-75) (r=-0.43, p<0.001) but not with LCI or FEV(0.5). CONCLUSION: Despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.

The EPICure study: association between hemodynamics and lung function at 11 years after extremely preterm birth.

OBJECTIVE: To investigate the relationship between disturbed lung function and large-artery hemodynamics in school-age children born extremely preterm (EP) (at 25 completed weeks of gestation or less). STUDY DESIGN: This was a cross-sectional study of participants from the EPICure study, now aged 11 years (n = 66), and 86 age- and sex-matched term-born classmates. Spirometry parameters (including forced expiratory volume in 1 second), blood pressure, and augmentation index (AIx, a composite of arterial stiffness and global wave reflections) were measured. RESULTS: Compared with their classmates, the EP children had significantly impaired lung function, particularly those with neonatal bronchopulmonary dysplasia. Peripheral blood pressure did not differ significantly between the 2 groups, but AIx values were on average 5% higher (95% CI, 2%-8%) in the preterm infants, remaining significant after adjustment for potential confounders. Neonatal bronchopulmonary dysplasia status was not related to AIx. Lung function and maternal smoking were independently associated with AIx; AIx increased by 2.7% per z-score reduction in baseline forced expiratory volume in 1 second and by 4.9% in those whose mothers smoked during pregnancy. CONCLUSION: The independent association between impaired lung function and cardiovascular physiology in early adolescence implies higher cardiovascular risk for children born EP, and suggests that prevention of chronic neonatal lung disease may be a priority in reducing later cardiovascular risk in preterm infants.

Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis.

RATIONALE: 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. OBJECTIVES: This study aimed to determine whether multiple-breath washout (MBW) results at preschool age can predict subsequent abnormal lung function. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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%. CONCLUSIONS: 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.

Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study.

RATIONALE: The long-term respiratory sequelae of infants born extremely preterm (EP) and now graduating from neonatal intensive care remains uncertain. OBJECTIVES: To assess the degree of respiratory morbidity and functional impairment at 11 years in children born EP (i.e., at or less than 25 completed weeks of gestation) in relation to neonatal determinants and current clinical status. METHODS: Pre- and postbronchodilator spirometry were undertaken at school in children born EP and classroom control subjects. Physical examination and respiratory health questionnaires were completed. Multivariable regression was used to estimate the predictive power of potential determinants of lung function. MEASUREMENTS AND MAIN RESULTS: Spirometry was obtained in 182 of 219 children born EP (129 with prior bronchopulmonary dysplasia [BPD]) and 161 of 169 classmates, matched for age, sex, and ethnic group. Children born EP had significantly more chest deformities and respiratory symptoms than classmates, with twice as many (25 vs. 13%; P < 0.01) having a current diagnosis of asthma. Baseline spirometry was significantly reduced (P < 0.001) and bronchodilator responsiveness was increased in those born EP, the changes being most marked in those with prior BPD. EP birth, BPD, current symptoms, and treatment with beta-agonists are each associated independently with lung function z-scores (adjusted for age, sex, and height) at 11 years. Fifty-six percent of children born EP had abnormal baseline spirometry and 27% had a positive bronchodilator response, but less than half of those with impaired lung function were receiving any medication. CONCLUSIONS: After extremely preterm birth, impaired lung function and increased respiratory morbidity persist into middle childhood, especially among those with BPD. Many of these children may not be receiving appropriate treatment.

The EPICure study: maximal exercise and physical activity in school children born extremely preterm.

RATIONALE: Evidence regarding exercise capacity and physical activity in children born extremely preterm (EP) is limited. Since survivors remain at high risk for developing bronchopulmonary dysplasia (BPD) and long-term pulmonary sequelae, reductions in exercise capacity and activity levels may be present. OBJECTIVES: To compare maximal exercise ventilation characteristics and physical activity levels at 11 years of age in children born EP (<25 completed weeks gestation) with those of full-term controls. METHODS: Participants performed spirometry, body plethysmography and gas transfer testing. A peak exercise test was performed on a cycle ergometer. Physical activity was monitored by accelerometry for 7 days. RESULTS: Lung function and exercise results were obtained in 38 EP children (71% prior BPD) and 38 controls. Those born EP had significantly lower Z-scores (mean (95% CI) of difference) for forced expiratory volume in 1 s (FEV(1); -1.74 (-2.25 to -1.23) and gas transfer (-0.73 (-1.31 to -0.17), and significantly greater Z-scores for residual volume (RV; 0.58 (0.10 to 1.10)) and RV/total lung capacity (TLC; 0.74 (0.29 to 1.19)). EP birth was associated with a significant reduction in peak oxygen consumption. EP children employed greater breathing frequencies and lower tidal volumes during peak exercise. No differences were observed in physical activity between groups. CONCLUSIONS: The reduction in peak oxygen consumption in children born EP, and alterations in ventilatory adaptations during peak exercise were not explained by differences in physical activity, but probably reflects the long-term pathophysiological impact of EP birth.