Influence of secular trends and sample size on reference equations for lung function tests.

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5-95 yrs. The best fit for forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18-227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV(1) and FVC from overall mean: 0.30- -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

Impaired lung compliance and DL,CO but no restrictive ventilatory defect in sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant manifestation in the lungs, often presenting as interstitial lung disease. Pulmonary function abnormalities in sarcoidosis include restriction of lung volumes, reduction in diffusing capacity of the lung for carbon monoxide (D(L,CO)), reduced static lung compliance (C(L,s)) and airway obstruction. The aim of the present study was to assess various lung function indices, including C(L,s) and D(L,CO), as markers of functional abnormality in sarcoidosis patients. Results from 830 consecutive patients referred for lung function tests with a diagnosis of sarcoidosis (223 in stage I, 486 in stage II and 121 in stage III) were retreospectively analysed. The mean ± sd age of the patients was 40 ± 11 yrs; 18% were active smokers and 24% were former smokers. Normal total lung capacity was found in 772 (93%) patients. Of these cases, 24.5% had a low C(L,s) and 21.5% had a low D(L,CO). At least one abnormality was observed in 39.3% of these patients, whereas, in restrictive patients, this figure was 88%. Airway obstruction was present in 11.7% of cases. Lung volumes usually remain within the normal range and measurement of either C(L,s) or D(L,CO) often reveal impaired lung function in sarcoidosis patients, even when their lung volumes are still in the normal range; these two measurements provide complementary information.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Pulmonary function and exercise capacity in survivors of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and pulmonary hypertension. The objective of this study was to assess pulmonary function and exercise capacity and its early determinants in children and adolescents born with high-risk CDH (CDH-associated respiratory distress within the first 24 h) and to explore the relationship of these findings with CDH severity. Of 159 patients born with high-risk CDH, 84 survived. Of the 69 eligible patients, 53 children (mean+/-SD age 11.9+/-3.5 yrs) underwent spirometry, lung volume measurements and maximal cardiopulmonary exercise testing (CPET). Results of the pulmonary function tests were compared with those from a healthy control group matched for sex, age and height. CDH survivors had a significantly lower forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), FEV(1)/FVC, maximum mid-expiratory flow and peak expiratory flow when compared with healthy controls. The residual volume/total lung capacity ratio was significantly higher. Linear regression analysis showed that gastro-oesophageal reflux disease was an independent determinant of reduced FEV(1) and FVC. CPET results were normal in those tested. High-risk CDH survivors have mild to moderate pulmonary function abnormalities when compared with a healthy matched control group, which may be related to gastro-oesophageal reflux disease in early life. Exercise capacity and gas exchange parameters were normal in those tested, indicating that the majority of patients do not have physical impairment.

Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction.

AIM: The prevalence of airway obstruction varies widely with the definition used. OBJECTIVES: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. METHODS: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) and its lower limit of normal (LLN) from the literature. FEV(1)/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17-90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV(1)/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. RESULTS: The LLN for FEV(1)/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995-1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17-45% of men and 7-26% of women for GOLD; 0-18% of men and 0-16% of women for ATS/ERS; and 0-9% of men and 0-11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. CONCLUSIONS: Airway obstruction should be defined by FEV(1)/FVC and FEV(1) being below the LLN using appropriate reference equations.

[Comments on screening spirometry for detection of COPD]. / Kanttekeningen bij screenend longfunctieonderzoek voor detectie van COPD.

World COPD day is an annual event intended to increase awareness of chronic obstructive pulmonary disease. During this day, in November 2006, free spirometry testing was offered to the public in approximately 100 places including hospitals, pharmacies, offices of GPs and tents on main squares throughout the Netherlands. The objective of this action is laudable. However, screening for COPD is generally considered ineffective. Furthermore, the application of a fixed ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) (FEV1/FVC < 0.70) as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to detect airflow limitation, required for a diagnosis of COPD, may lead to underdiagnosis of COPD in the young and to overdiagnosis in the elderly. In addition, spirometry was generally performed without bronchodilation, thus further increasing the likelihood of a false-positive diagnosis ofCOPD. Smoking cessation is important in halting the progression of COPD. Therefore, identifying smokers at risk for developing COPD seems a logical reason for screening or case finding for COPD. However, it has not been clearly demonstrated that early detection of COPD may contribute to improved smoking cessation rates. Also, smokers with normal spirometry may be led to believe that smoking has no adverse effects on their health. Therefore, a different strategy should be adopted to increase awareness of COPD on the next World COPD day.

Inhaled corticosteroids and growth of airway function in asthmatic children.

Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinally whether asthma affects growth of airway function relative to airspaces, and if so whether this is redressed by inhaled corticosteroids (ICS). Every 4 months for up to 3 yrs, lung function was assessed in 54 asthmatic children (initial age 7-16 yrs), who inhaled 0.2 mg salbutamol t.i.d. and 0.2 mg budesonide t.i.d. (beta2-agonist (BA)+ICS), or placebo (PL) t.i.d. (BA+PL) in a randomised, double-blind design. Measurements were carried out before and after maximal bronchodilation. Airway growth was assessed from the change of forced expiratory volume in one second and of maximal expiratory flows (at 60% and 40% of total lung capacity (TLC) remaining in the lung) relative to TLC, as measures of more central, intermediate and more peripheral airways. Growth patterns were compared with the longitudinal findings in 376 healthy children. Airway patency after maximal bronchodilation in patients on BA+PL remained reduced compared to healthy subjects, whereas in patients on BA+ICS a marked improvement was observed to subnormal. No differences between patients and controls could be demonstrated for growth patterns of central and intermediate airway function. Compliance with BA+ICS was 75% of the prescribed dose, resulting in significant, sustained improvement of symptoms and postbronchodilator calibre of central and intermediate airways to subnormal within 2 months, but postbronchodilator small airway patency remained reduced, though improved compared to patients on BA+PL. Anti-inflammatory treatment of asthmatic children is associated with normal functional development of central and intermediate airways. The persistently reduced postbronchodilator patency of peripheral airways may reflect remodelling, or insufficient anti-inflammatory treatment.

Peak expiratory flow profiles delivered by pump systems. Limitations due to wave action.

Pump systems are currently used to test the performance of both spirometers and peak expiratory flow (PEF) meters, but for certain flow profiles the input signal (i.e., requested profile) and the output profile can differ. We developed a mathematical model of wave action within a pump and compared the recorded flow profiles with both the input profiles and the output predicted by the model. Three American Thoracic Society (ATS) flow profiles and four artificial flow-versus-time profiles were delivered by a pump, first to a pneumotachograph (PT) on its own, then to the PT with a 32-cm upstream extension tube (which would favor wave action), and lastly with the PT in series with and immediately downstream to a mini-Wright peak flow meter. With the PT on its own, recorded flow for the seven profiles was 2.4 +/- 1.9% (mean +/- SD) higher than the pump's input flow, and similarly was 2.3 +/- 2.3% higher than the pump's output flow as predicted by the model. With the extension tube in place, the recorded flow was 6.6 +/- 6.4% higher than the input flow (range: 0.1 to 18.4%), but was only 1.2 +/- 2.5% higher than the output flow predicted by the model (range: -0.8 to 5.2%). With the mini-Wright meter in series, the flow recorded by the PT was on average 6.1 +/- 9.1% below the input flow (range: -23.8 to 2. 5%), but was only 0.6 +/- 3.3% above the pump's output flow predicted by the model (range: -5.5 to 3.9%). The mini-Wright meter's reading (corrected for its nonlinearity) was on average 1.3 +/- 3.6% below the model's predicted output flow (range: -9.0 to 1. 5%). The mini-Wright meter would be deemed outside ATS limits for accuracy for three of the seven profiles when compared with the pump's input PEF, but this would be true for only one profile when compared with the pump's output PEF as predicted by the model. Our study shows that the output flow from pump systems can differ from the input waveform depending on the operating configuration. This effect can be predicted with reasonable accuracy using a model based on nonsteady flow analysis that takes account of pressure wave reflections within pump systems.

Functional residual capacity and static compliance during the first year in preterm infants treated with surfactant.

Individual lung development during the first year of life was studied in surfactant treated preterm infants with respiratory distress syndrome (RDS) and healthy controls, as well as in a group who subsequently developed chronic lung disease of the newborn (CLDN). Lung development was assessed from functional residual capacity (FRC) and compliance of the respiratory system (Crs). Twenty-one infants with RDS after preterm birth received surfactant treatment. Six of them developed CLDN. Eighteen preterm infants without RDS served as a control group. Lung function measurements were performed at term age and 4, 8, and 12 months afterwards. FRC was obtained by means of the closed-system helium dilution technique whereas static Crs was obtained by means of the weighted spirometer technique. At term age, FRC was lower in the CLDN group compared with uncomplicated RDS and controls (p < 0.05). No significant differences between groups were found in the development of FRC during the first year of life (p = 0.4). No differences were found in Crs during the first year of life in surfactant treated infants who recovered from uncomplicated RDS and the control group. However, lower values were found in the CLDN group (p < 0.05). We conclude that surfactant treated infants without CLDN have similar lung development during the first year of life as control preterm infants.

Diurnal variation in lung function in subgroups from two Dutch populations: consequences for longitudinal analysis.

We studied circadian variation in FVC, FEV1, PEF, TLC, VC, and RV between 9:00 A.M. and 9:00 P.M. and analyzed how this variation affected estimated longitudinal change. Data from 876 adults were obtained in a longitudinal survey of samples from two Dutch areas. Subjects participated in four surveys held at 3-yr intervals between 1975 and 1985. FVC, FEV1, PEF, and VC increased from 9:00 A.M. until noon and decreased afterwards. TLC was constant over the day, whereas RV decreased from 9:00 A.M. to noon. Average variation in FVC, FEV1 and PEF, expressed as percentages of average level, was 4. 8% (200 ml), 2.8% (86 ml), and 3.1% (250 ml/s), respectively. These results are compatible with circadian changes in airway size. No differences in variability were found between men and women. Significantly larger changes between 9:00 A.M. and noon were found in young adults, smokers, and those with respiratory symptoms than in other subgroups. Adjustment for diurnal variation reduced, albeit slightly, residual standard deviations of estimated longitudinal declines. Average diurnal change was large relative to underlying longitudinal change. Its effect on longitudinal change within an individual can therefore be large depending on age, smoking habits, symptomatology, number of visits, time of measurement, and difference in time between measurements. However, when people are measured at random times during the day for at least three visits, or when measurements are made after 11:00 A.M., effects of diurnal variation in pulmonary function on estimated average longitudinal decline are minimal.

Determination of diffusing capacity by modeling the dynamics of C18O uptake in newborns.

Dynamic modeling of lung C18O diffusion is used to measure the C18O transfer factor (TLCO) of 14 newborns aged 1-4 mo. The model equation is based on the alveolar fractions of C18O and on changing alveolar ventilation induced by the rebreathing conditions. The model does not involve the volume of the rebreathing bag which is usually needed when applying rebreathing technique and which is a source of error. The equation is discretized and solved for recorded data obtained with equipment adapted to use in newborns. A least-square parameter calculation technique is applied to estimate TLCO. Results show a strong relationship between this index and the biometrical ones and confirm those found in the literature featuring that the measurement duration can be considerably shortened.

References values for forced spirometry. Group of the European Community Respiratory Health Survey.

The European Coal and Steel Community (ECSC) prediction equations exemplify a significant effort carried out approximately 15 yrs ago to provide uniform standards for lung function testing, but this set of equations has not been properly validated as yet. The present study evaluates the ECSC reference values and four other sets of prediction equations, using spirometric data collected in 12,900 nonasthmatic subjects (43% lifetime nonsmokers and 36% active smokers) aged 20-44 yrs from the European Community Respiratory Health Survey (ECRHS). Standardized spirometric measurements were obtained using a common protocol in 34 centres in 14 countries. For each prediction equation, the prediction deviations (i.e. observed minus predicted value) for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined for the whole study population and for each centre. For the age range included, the errors about the ECSC equations showed the most prominent underestimation of both predicted FVC (+355 and +360 mL on average in males and females, respectively) and predicted FEV1 (+211 and +200 mL, respectively) among the five studies examined. As expected, FVC and FEV1 in active smokers from the ECRHS were significantly lower than in lifetime nonsmokers (each p<0.01). We conclude that the present European recommendations on lung function reference values should be reconsidered, but further data for nonsymptomatic subjects above the age of 44 yrs are needed.

The rise and dwell time for peak expiratory flow in patients with and without airflow limitation.

The response of peak expiratory flow (PEF) meters may be affected by the magnitude of PEF, the time taken to get to PEF, and the duration that the peak is sustained. We undertook a retrospective study to define the 10 to 90% rise time (RT) and dwell time for flow above 90% (DT90) and 95% (DT95) of PEF. Blows were analyzed that had been recorded using a pneumotachograph from 912 patients older than 17 yr of age (556 men) who routinely attended a lung function laboratory. For each subject, that blow with the largest PEF was used to derive the PEF, FEV1, FVC, RT, DT90, and DT95. The values for RT, DT90, and DT95 were negatively skewed with the median values for men of 58, 29, and 19 ms, respectively, being significantly shorter than those for the women of 67, 49, and 31 ms. From the 912 subjects, there were 277 (153 men) who had all their spirometric indices within the normal range, and 305 (220 men) had both PEF and FEV1 more than 1. 645 SD below predicted, indicating airflow limitation. For subjects with airflow limitation the median RT was significantly smaller than in the normal subjects (men: 46 versus 72 ms, women: 50 versus 72 ms), and the same was found for DT90 (men: 22 versus 40 ms, women: 27 versus 56 ms) and DT95 (men: 15 versus 26 ms, women: 18 versus 34 ms). We conclude that the dwell times for PEF are shorter in men, and the rise and dwell times are shorter in patients with airflow limitation. Profiles used to test PEF meters should encompass the range of rise and dwell times found in subjects most likely to be using PEF meters, that is, those with airflow limitation.

Pulmonary function in infants with neonatal chronic lung disease with or without hyaline membrane disease at birth.

We studied whether neonatal chronic lung disease (NCLD), hyaline membrane disease (HMD) and differences in ventilatory support affected pulmonary function during the first year of life, in 65 infants born prematurely. The relationship between body weight and oxygen consumption (V'O2) was also analysed. The study comprised 14 infants without cardiorespiratory disease, 19 infants with HMD but without NCLD, 9 infants with NCLD without prior HMD, and 23 infants with NCLD following HMD. At 6 and 12 months corrected postnatal age, static respiratory system compliance (Crs) was measured by weighted spirometry and the functional residual capacity by closed circuit helium dilution (FRCHe) combined with assessment of ventilation distribution from the mixing index (MI). Ventilatory support during the first 5 days of therapy was quantified from peak inspiratory pressure (PIP), mean airway pressure (MAP) and fractional inspiratory concentration of oxygen (FI,O2). Infants with NCLD had a shorter duration of gestation and lower birth weight than those without NCLD (Wilcoxon, p=0.002 and p=0.001, respectively). Pulmonary function at 6 and 12 months corrected age was not different between NCLD infants with or without HMD at birth. Infants with NCLD had lower Crs and MI than those without NCLD (analysis of variance (ANOVA), p<0.011), but their FRCHe was not different. V'O2 adjusted for body weight was comparable in the four groups. PIP and FI,O2 were higher (Wilcoxon, p<0.01) in the NCLD infants than in those with HMD alone, but MAP was not different. Except for FI,O2, these indices were not different among the infants with NCLD. We conclude that birth weight is the major determinant of the development of neonatal chronic lung disease. At 6 and 12 months corrected age, the abnormal pulmonary function is not associated with prior hyaline membrane disease.