Global Lung Function Initiative Reference Research Articles

Changes in FEV1 over time in COPD and the importance of spirometry reference ranges: the devil is in the detail.

A discussion of two landmark papers highlighting the use of spirometry as a sensitive measure of the rate of decline in FEV1 in COPD, and the importance of using the Global Lung Function Initiative reference data http://bit.ly/2C0Nhqa

Reference equations for spirometry in healthy Asian children aged 5 to 18 years in Taiwan

Background and objectiveThis study aimed to establish reference equations for spirometry in healthy Taiwanese children and assess the applicability of the Global Lung Function Initiative (GLI)-2012 equations to Taiwanese children. MethodsSpirometric data collected from 757 healthy Taiwanese children aged 5 to 18 years in a population-based cohort study. Prediction equations derived using linear regression and the generalized additive models for location, scale and shape (GAMLSS) method, respectively. ResultsThe GLI-2012 South East Asian equations did not provide a close fit with mean ± standard error z-scores of −0.679 ± 0.030 (FVC), −0.186 ± 0.044 (FEV1), −0.875 ± 0.049 (FEV1/FVC ratio) and −2.189 ± 0.063 (FEF25-75) for girls; and 0.238 ± 0.059, −0.061 ± 0.053, −0.513 ± 0.059 and −1.896 ± 0.077 for boys. The proposed GAMLSS models took age, height, and weight into account. GAMLSS models for boys and girls captured the characteristics of spirometric data in the study population closely in contrast to the linear regression models and the GLI-2012 equations. ConclusionThis study provides up-to-date reference values for spirometry using GAMLSS modeling in healthy Taiwanese children aged 5 to 18 years. Our study provides evidence that the GLI-2012 reference equations are not properly matched to spirometric data in a contemporary Taiwanese child population, indicating the urgent need for an update of GLI reference values by inclusion of more data of non-Caucasian decent.

Low resting diffusion capacity, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease.

The mechanisms linking reduced diffusing capacity of the lung for carbon monoxide (DlCO) to dyspnea and exercise intolerance across the chronic obstructive pulmonary disease (COPD) continuum are poorly understood. COPD progression generally involves both DlCO decline and worsening respiratory mechanics, and their relative contribution to dyspnea has not been determined. In a retrospective analysis of 300 COPD patients who completed symptom-limited incremental cardiopulmonary exercise tests, we tested the association between peak oxygen-uptake (V̇o2), DlCO, and other resting physiological measures. Then, we stratified the sample into tertiles of forced expiratory volume in 1 s (FEV1) and inspiratory capacity (IC) and compared dyspnea ratings, pulmonary gas exchange, and respiratory mechanics during exercise in groups with normal and low DlCO [i.e., <lower limit of normal (LLN)] using Global Lung Function Initiative reference values. DlCO was associated with peak V̇o2 (P = 0.006), peak work-rate (P = 0.005), and dyspnea/V̇o2 slope (P < 0.001) after adjustment for other independent variables (airway obstruction and hyperinflation). Within FEV1 and IC tertiles, peak V̇o2 and work rate were lower (P < 0.05) in low versus normal DlCO groups. Across all tertiles, low DlCO groups had higher dyspnea ratings, greater ventilatory inefficiency and arterial oxygen desaturation, and showed greater mechanical volume constraints at a lower ventilation during exercise than the normal DlCO group (all P < 0.05). After accounting for baseline resting respiratory mechanical abnormalities, DlCO<LLN was consistently associated with greater dyspnea and poorer exercise performance compared with preserved DlCO. The higher dyspnea ratings and earlier exercise termination in low DlCO groups were linked to significantly greater pulmonary gas exchange abnormalities, higher ventilatory demand, and associated accelerated dynamic mechanical constraints.NEW & NOTEWORTHY Our study demonstrated that chronic obstructive pulmonary disease patients with diffusing capacity of the lung for carbon monoxide (DlCO) less than the lower limit of normal had greater pulmonary gas exchange abnormalities, which resulted in higher ventilatory demand and greater dynamic mechanical constraints at lower ventilation during exercise. This, in turn, led to greater exertional dyspnea and exercise intolerance compared with patients with normal DlCO.

Do the global lung function initiative reference equations reflect a sample of adult Middle Eastern population?

The global lung function initiative (GLI) 2012 introduced new multi-ethnic spirometry reference values for numerous ethnicities. The aim of this study was to investigate the suitability of the GLI reference values for the adult Jordanian population. About 1875 (1029 females and 846 males) healthy non-smoking adults were enrolled from several locations in Jordan. Spirometry tests were performed. z-scores and predicted normal values were calculated for each participant using GLI 2012 equations in addition to other local equations from the Middle East. Our results indicated that none of the GLI 2012 or other regional equations studied produced an acceptable fit to our data. A need to formulate a specific equation for the Jordanian population is urgently required to better evaluate their respiratory conditions.

Collating Spirometry reference values in Asian children and Adolescents; puzzle out the reasons for variations.

Lung function tests are essential for the diagnosis and management of different respiratory tract diseases; among them the spirometry is the gold standard technique. The accurate diagnosis, management and monitoring require proper interpretation of the results which depends upon the availability of spirometry reference data for that particular region to differentiate the diseased condition from the normal ones. Multiple studies had been done to find out their own area specific reference ranges but it is still lacking. This need was fulfilled by the Global Lung Function Initiative (GLI) in 2012, which reported the first global spirometry equation for all of the age groups. But some of the studies reported difference among GLI reference range and the measured range for that particular region. So here is the review of the reference ranges among 35,603 Asian children and adolescents from the 32 studies done specifically in Asia. The aim was to compare them with the study done by GLI team, along with these, tried to rule out the causal factor that are responsible for the variations in the reference ranges among the children and adolescents of different population. The literature was searched by using Google scholar and PubMed during the month of March up to July 2017.The review of all the articles published in Asia, specifically accounting for normal reference ranges in children and adolescent exhibit a wide variation among the reference ranges. This also suggest involvement of multiple modifiable and non-modifiable risk factors. So it’s necessary to update the reference ranges for spirometry and its prediction equation as well.

The Global Lung Function Initiative (GLI) Network: bringing the world's respiratory reference values together.

The Global Lung Function Initiative (GLI) Network has become the largest resource for reference values for routine lung function testing ever assembled. This article addresses how the GLI Network came about, why it is important, and its current challenges and future directions. It is an extension of an article published in Breathe in 2013 [1], and summarises recent developments and the future of the GLI Network.Key pointsThe Global Lung Function Initiative (GLI) Network was established as a result of international collaboration, and altruism between researchers, clinicians and industry partners. The ongoing success of the GLI relies on network members continuing to work together to further improve how lung function is reported and interpreted across all age groups around the world.The GLI Network has produced standardised lung function reference values for spirometry and gas transfer tests.GLI reference equations should be adopted immediately for spirometry and gas transfer by clinicians and physiologists worldwide.The recently established GLI data repository will allow ongoing development and evaluation of reference values, and will offer opportunities for novel research.Educational aimsTo highlight the advances made by the GLI Network during the past 5 years.To highlight the importance of using GLI reference values for routine lung function testing (e.g. spirometry and gas transfer tests).To discuss the challenges that remain for developing and improving reference values for lung function tests.

Global Lung Function Initiative 2012 reference values for spirometry in South Italian children.

Despite the widespread use of the Global Lung Function Initiative (GLI) 2012 reference values, there is still the need of testing their applicability in local areas. The aims of this study are to evaluate applicability of GLI reference equations in a large population-based sample of normal schoolchildren from Sicily, and to compare GLI and previous prediction equations in terms of spirometry test interpretation. GLI equations were evaluated in 1243 normal schoolchildren, 49% males, aged 7-16 years, height 116-187cm. Normality assumptions for the GLI z-scores (FEV1, FVC, FEV1/FVC) were tested, and bootstrap confidence intervals for the mean (0 expected) and the variance (1 expected) were derived. GLI and other reference equations were compared in terms of probabilities to fall below the lower limit of normal (LLN). The GLI z-score normality assumption held for males but not for females (p<0.001). According to the mean z-score, predicted values were: slightly underestimated for FEV1 (0.15 in males, 0.07 in females); overestimated for FVC (-0.27 in males,-0.32 in females); highly underestimated for FEV1/FVC (0.75 in males, 0.81 in females). Variability was correctly estimated. The probability of FEV1<LLN correctly approached 0.05 when using GLI, Hankinson and Quanjer equations. Wang equations yielded correct probabilities of abnormal FVC; Pistelli equations yielded correct probabilities of abnormal FEV1/FVC for females. GLI 2012 references underestimate FEV1/FVC predicted values in a sample of normal South Italian children. Physicians interpreting spirometry should be aware to test reference values prior to their use in a local area.

Long-term effects of severe acute malnutrition on lung function in Malawian children: a cohort study.

Early nutritional insults may increase risk of adult lung disease. We aimed to quantify the impact of severe acute malnutrition (SAM) on spirometric outcomes 7 years post-treatment and explore predictors of impaired lung function.Spirometry and pulse oximetry were assessed in 237 Malawian children (median age: 9.3 years) who had been treated for SAM and compared with sibling and age/sex-matched community controls. Spirometry results were expressed as z-scores based on Global Lung Function Initiative reference data for the African–American population.Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were low in all groups (mean FEV1 z-score: −0.47 for cases, −0.48 for siblings, −0.34 for community controls; mean FVC z-score: −0.32, −0.38, and −0.15 respectively). There were no differences in spirometric or oximetry outcomes between SAM survivors and controls. Leg length was shorter in SAM survivors but inter-group sitting heights were similar. HIV positive status or female sex was associated with poorer FEV1, by 0.55 and 0.31 z-scores, respectively.SAM in early childhood was not associated with subsequent reduced lung function compared to local controls. Preservation of sitting height and compromised leg length suggest “thrifty” or “lung-sparing” growth. Female sex and HIV positive status were identified as potentially high-risk groups.

GOLD criteria overestimate airflow limitation in one-third of cases in the general Finnish population

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria for chronic obstructive pulmonary disease (COPD) use a fixed threshold of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (<0.70) in post-bronchodilation spirometry to indicate disease, which has been shown to underestimate and overestimate disease prevalence in younger and older adults, respectively, whilst criteria based on reference values have better accuracy. Differences in reference values have limited their use in international studies. However, the new Global Lung Function Initiative reference values (GLI2012) showed FEV1/FVC to be the least dependent on ethnicity. The aim of this study was to assess the prevalence of airflow limitation with GLI2012 and the degree of underdetection or overestimation related to the use of GOLD in the general population.A Finnish population sample of 1323 subjects (45% male) with post-bronchodilation spirometry was studied.80 subjects (6.0%) and 55 subjects (4.2%) were identified with airflow limitation with GOLD and GLI2012 criteria, respectively. The proportion of overestimation with GOLD increased with age from 25% of cases in 50-year-olds to 54% in 70-year-olds. Using z-score-based grading resulted in more dispersion in severity grading.In conclusion, the GOLD criteria cause a marked overestimation already from 50-year-olds and should be replaced with the GLI2012 criteria to improve diagnostic accuracy.

Prevalence of abnormal findings when adopting new national and international Global Lung Function Initiative reference values for spirometry in the Finnish general population

BackgroundNew Finnish (Kainu2015) and international Global Lung Function Initiative (GLI2012) reference values for spirometry were recently published. The aim of this study is to compare the interpretative consequences of adopting these new reference values with older, currently used Finnish reference values (Viljanen1982) in the general population of native Finns.MethodsTwo Finnish general population samples including 1,328 adults (45% males) aged 21–74 years were evaluated. Airway obstruction was defined as a reduced ratio of forced expiratory volume in one second (FEV1)/forced vital capacity (FVC), possible restrictive pattern as reduced FVC, and decreased ventilatory capacity as reduced FEV1 below their respective 2.5th percentiles. The severity gradings of reduced lung function were also compared.ResultsUsing the Kainu2015 reference values, the prevalence of airway obstruction in the population was 5.6%; using GLI2012 it was 4.0% and with Viljanen1982 it was 13.0%. Possible restrictive pattern was found in 4.2% using the Kainu2015 values, in 2.0% with GLI2012, and 7.9% with the Viljanen1982 values. The prevalence of decreased ventilatory capacity was 6.8, 4.0, and 13.3% with the Kainu2015, GLI2012 and Viljanen1982 values, respectively.ConclusionsThe application of the GLI2012 reference values underestimates the prevalence of abnormal spirometric findings in native Finns. The adoption of the Kainu2015 reference values reduces the prevalences of airways obstruction, decreased ventilatory capacity, and restrictive impairment by approximately 50%. Changing from the 2.5th percentile, the previously used lower limit of normal, to the 5th percentile recommended by the American Thoracic Society/European Respiratory Society will not increase the prevalence of abnormal findings in the implementation of spirometry reference values.

Implications of the Transition From Zapletal to GLI Reference Values for Spirometry.

The current standard for monitoring lung function in children with asthma is spirometry. In Europe, results of these lung function tests have been related to Zapletal reference values published in 1977. Recently, the Global Lung Function Initiative (GLI) published predicted values of spirometry for 5 ethnic groups, valid over an age range from 3 to 95 years. These reference values have been approved by many international lung societies, and the algorithms are increasingly being implemented globally. This report describes the consequences of the transition from Zapletal reference values to GLI reference values for 2 pediatric asthma patients, which include unexpected declines in lung function and the ability to take advantage of newly approved reimbursement for advanced therapy. The Zapletal and GLI reference values cannot be used interchangeably, and transition to the GLI values might lead to better treatment in the future.

Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults.

Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values.

Reference values for spirometry – report from the Obstructive Lung Disease in Northern Sweden studies

BackgroundAbnormal lung function is commonly identified by comparing observed spirometric values to corresponding reference values. It is recommended that such reference values for spirometry are evaluated and updated frequently. The aim of this study was to estimate new reference values for Swedish adults by fitting a multivariable regression model to a healthy non-smoking general population sample from northern Sweden. Further aims were to evaluate the external validity of the obtained reference values on a contemporary sample from south-western Sweden, and to compare them to the Global Lung Function Initiative (GLI) reference values.MethodSex-specific multivariable linear regression models were fitted to the spirometric data of n=501 healthy non-smoking adults aged 22–91 years, with age and height as predictors. The models were extended to allow the scatter around the outcome variable to depend on age, and age-dependent spline functions were incorporated into the models to provide a smooth fit over the entire age range. Mean values and lower limits of normal, defined as the lower 5th percentiles, were derived.ResultThis modelling approach resulted in unbiased estimates of the spirometric outcomes, and the obtained estimates were appropriate not only for the northern Sweden sample but also for the south-western Sweden sample. On average, the GLI reference values for forced expiratory volume in one second (FEV1) and, in particular, forced expiratory vital capacity (FVC) were lower than both the observed values and the new reference values, but higher for the FEV1/FVC ratio.ConclusionThe evaluation based on the sample of healthy non-smokers from northern Sweden show that the Obstructive Lung Disease in Northern Sweden reference values are valid. Furthermore, the evaluation based on the south-western Sweden sample indicates a high external validity. The comparison with GLI brought further evidence to the consensus that, when available, appropriate local population-specific reference values may be preferred.

S66 The Gli Spirometry Reference Equations Influence The Apparent Rate Of Decline In Fev1 Among Children And Adolescents With Cystic Fibrosis

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.

Irreversible airway obstruction in adulthood after bronchiolitis in infancy: Evidence from a 30-year follow-up study

Lower respiratory infections in infancy may be associated with lung function deficits in adulthood. Our aim was to evaluate lung function, with a special focus on irreversible airway obstruction, thirty years after bronchiolitis or pneumonia in infancy. In 1981-1982, 83 children under two years of age were hospitalized for bronchiolitis and 44 for pneumonia at Kuopio University Hospital, Finland. In 2010, 47 bronchiolitis patients, 22 pneumonia patients and 138 controls attended the study, including spirometry before (pre-BD) and after bronchodilatation (post-BD). The measured indices were forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), that were presented as % of predicted value (FVC% and FEV1%). FEV1/FVC was presented as both absolute FVC/FEV1-ratio and % of predicted (FEV1/FVC%). Irreversible airway obstruction was defined as post-BD FEV1/FVC% below 88% of predicted (FEV1/FVC% <88%) according to Finnish reference values or FEV1/FVC-ratio below fifth percentile (FEV1/FVC <5th percentile), according to Global Lung Function Initiative reference values. All lung function indices were lower in former bronchiolitis patients and pre- and post-BD FEV1% in pneumonia patients, compared to controls. 21% of bronchiolitis (OR, 95%CI; 5.59, 1.72-18.21) and 9% of pneumonia patients (2.24, 0.34-13.56) had FEV1/FVC% <88% compared to controls (4%). Likewise 7 (15%) of bronchiolitis (7.07, 1.33-37.22) and 1 (5%) of pneumonia patients (1.73, 0.12-24.77) had FEV1/FVC <5th percentile compared to controls 2 (1%). Evidence of reduced lung function was present 30 years after hospitalization for bronchiolitis or pneumonia in infancy. Irreversible airway obstruction after severe bronchiolitis in infancy suggests permanent, structural alterations in airways.

S33 Validation of the GLI-2012 Multi-Ethnic Spirometry Reference Equations in London School Children

The Global Lung Function Initiative (GLI) recently published the first global all-age (3–95 years) multi-ethnic reference equations for spirometry (Quanjer 2012 ERJ). <h3>Aim</h3> To assess the agreement of the GLI reference range to contemporary lung function data from children living in Britain to verify its appropriateness for clinical use in this population. <h3>Methods</h3> Anthropometry and spirometry were undertaken within a mobile laboratory in primary school children recruited to the Size and Lung function In Children study during one school year (2011–2012). Spirometry Z-scores were calculated using the GLI-2012 reference range, using the ‘Black equation’ for South Asian children, for whom a specific equation has yet to be developed. <h3>Results</h3> Spirometry data from 728 (47% boys; 35% White; 28% Black; 26% South Asian; 11% other/mixed race) healthy children aged 5–11 years from eight London schools were eligible for inclusion. Mean (SD) age of 8 (1.6) years was similar across the 4 ethnic groups. After adjustment for age and sex, Black children were significantly heavier and taller compared to other groups, while South Asians were significantly lighter. When compared with White children, after adjusting for age, sex and standing height, FEV1 was significantly lower by a mean(95%CI) of 14% (11%; 16%) in Black; 11% (9%; 14%) in South Asian and 4% (1%; 8%) in the “other”/mixed race children. Similar patterns were seen for FVC but FEV1/FVC was similar across all groups. When expressed according to ethnic-specific reference equations the mean (SD) for FVC, FEV1 and FEV1/FVC for the White, Black and other groups approximated 0(1) suggesting that the GLI equations are appropriate for use in this population (Figure). Mean (95%CI) FVC and FEV1 were however 3% (–0.1%; 6.1%, p=0.07) higher in South Asian than Black children. <h3>Conclusions</h3> This study shows that the GLI-2012 equations are appropriate for use in children across a wide range of ethnicities. Of the currently available equations, the ‘Black equation’ provides the best fit for South Asian children, although it results in slight over-estimation of lung function, emphasising the need to develop specific coefficients for this group.