Janet Stocks

Multi-ethnic reference values for spirometry for the 3-95-yr age range: The global lung function 2012 equations

The aim of the Task Force was to derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally. Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5–95 yrs. Lung function data were collated and prediction equations derived using the LMS method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family. After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals aged 3–95 yrs for Caucasians (n=57,395), African–Americans (n=3,545), and North (n=4,992) and South East Asians (n=8,255). Forced expiratory value in 1 s (FEV1) and forced vital capacity (FVC) between ethnic groups differed proportionally from that in Caucasians, such that FEV1/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed. Spirometric prediction equations for the 3–95-age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent and Arabic, Polynesian and Latin American countries, as well as Africa will further improve these equations in the future.

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 (FEV1/FVC) and its lower limit of normal (LLN) from the literature. FEV1/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 FEV1/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 FEV1/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 FEV1/FVC and FEV1 being below the LLN using appropriate reference equations.

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.

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.

GREIT: A unified approach to 2D linear EIT reconstruction of lung images

Electrical impedance tomography (EIT) is an attractive method for clinically monitoring patients during mechanical ventilation, because it can provide a non-invasive continuous image of pulmonary impedance which indicates the distribution of ventilation. However, most clinical and physiological research in lung EIT is done using older and proprietary algorithms; this is an obstacle to interpretation of EIT images because the reconstructed images are not well characterized. To address this issue, we develop a consensus linear reconstruction algorithm for lung EIT, called GREIT (Graz consensus Reconstruction algorithm for EIT). This paper describes the unified approach to linear image reconstruction developed for GREIT. The framework for the linear reconstruction algorithm consists of (1) detailed finite element models of a representative adult and neonatal thorax, (2) consensus on the performance figures of merit for EIT image reconstruction and (3) a systematic approach to optimize a linear reconstruction matrix to desired performance measures. Consensus figures of merit, in order of importance, are (a) uniform amplitude response, (b) small and uniform position error, (c) small ringing artefacts, (d) uniform resolution, (e) limited shape deformation and (f) high resolution. Such figures of merit must be attained while maintaining small noise amplification and small sensitivity to electrode and boundary movement. This approach represents the consensus of a large and representative group of experts in EIT algorithm design and clinical applications for pulmonary monitoring. All software and data to implement and test the algorithm have been made available under an open source license which allows free research and commercial use.

Long-term impact of neonatal intensive care and surgery on somatosensory perception in children born extremely preterm

Abstract Alterations in neural activity due to pain and injury in early development may produce long‐term effects on sensory processing and future responses to pain. To investigate persistent alterations in sensory perception, we performed quantitative sensory testing (QST) in extremely preterm (EP) children (n = 43) recruited from the UK EPICure cohort (born less than 26 weeks gestation in 1995) and in age and sex matched term‐born controls (TC; n = 44). EP children had a generalized decreased sensitivity to all thermal modalities, but no difference in mechanical sensitivity at the thenar eminence. EP children who also required neonatal surgery had more marked thermal hypoalgesia, but did not differ from non‐surgical EP children in the measures of neonatal brain injury or current cognitive ability. Adjacent to neonatal thoracotomy scars there was a localized decrease in both thermal and mechanical sensitivity that differed from EP children with scars relating to less invasive procedural interventions or from those without scars. No relationship was found between sensory perception thresholds and current pain experience or pain coping styles in EP or TC children. Neonatal care and surgery in EP children are associated with persistent modality‐specific changes in sensory processing. Decreases in mechanical and thermal sensitivity adjacent to scars may be related to localized tissue injury, whereas generalized decreases in thermal sensitivity but not in mechanical sensitivity suggest centrally mediated alterations in the modulation of C‐fibre nociceptor pathways, which may impact on responses to future pain or surgery.

Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis

Background: 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. Methods: 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. Results: 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 (⩾−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) Conclusions: MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.

Spirometry centile charts for young Caucasian children: The asthma UK collaborative initiative

RATIONALE 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. OBJECTIVES 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. METHODS 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. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS We present prediction equations for spirometry for preschool children and provide a foundation that will facilitate continued updating.

Reference values for lung function: past, present and future

Reliable interpretation of pulmonary function results relies on the availability of appropriate reference data to help distinguish between health and disease and to assess the severity and nature of any functional impairment. The overwhelming number of published reference equations, with at least 15 published for spirometry alone in the past 3 yrs, complicates the selection of an appropriate reference. The use of inappropriate reference equations and misinterpretation, even when potentially appropriate equations are used, can lead to serious errors in both under and over diagnosis, with its associated burden in terms of financial and human costs. Further misdiagnosis occurs when fixed cut-offs, such as 80% predicted forced expiratory volume in 1 s (FEV1) or 0.70 FEV1/forced vital capacity, are used; particularly in young children and elderly adults. While per cent predicted has historically been used to interpret lung function results, z-scores are more appropriate as they take into account the predicted value, as well as the between-subject variability of measurements. We aim to highlight some of the main issues in selecting and using reference equations and discuss how recent developments may improve interpretation of pulmonary function results.

Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests

Background: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. Objectives: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco–abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. Methods: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. Results: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV0.5 and FEF25–75 ) than boys (mean (95% CI girls–boys): –1.2 (–2.1 to −0.3) for FEV0.5 Z score; FEF25–75: –1.2 (–2.2 to −0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. Conclusions: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.