ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

Global, Race-Neutral Reference Equations and Pulmonary Function Test Interpretation.

Importance: Race and ethnicity are routinely used to inform pulmonary function test (PFT) interpretation. However, there is no biological justification for such use, and it may reinforce health disparities. Objective: To compare the PFT interpretations produced with race-neutral and race-specific equations. Design, Setting, and Participants: In this cross-sectional study, race-neutral reference equations recently developed by the Global Lung Function Initiative (GLI) were used to interpret PFTs performed at an academic medical center between January 2010 and December 2020. The interpretations produced with these race-neutral reference equations were compared with those produced using the race and ethnicity-specific reference equations produced by GLI in 2012. The analysis was conducted from April to October 2022. Main Outcomes and Measures: The primary outcomes were differences in the percentage of obstructive, restrictive, mixed, and nonspecific lung function impairments identified using the 2 sets of reference equations. Secondary outcomes were differences in severity of these impairments. Results: PFTs were interpreted from 2722 Black (686 men [25.4%]; mean [SD] age, 51.8 [13.9] years) and 5709 White (2654 men [46.5%]; mean [SD] age, 56.4 [14.3] years) individuals. Among Black individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with an increase in the prevalence of restriction from 26.8% (95% CI, 25.2%-28.5%) to 37.5% (95% CI, 35.7%-39.3%) and of a nonspecific pattern of impairment from 3.2% (95% CI, 2.5%- 3.8%) to 6.5% (95% CI, 5.6%-7.4%) and no significant change in the prevalence of obstruction (19.9% [95% CI, 18.4%-21.4%] vs 19.5% [95% CI, 18.0%-21.0%]). Among White individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with a decrease in the prevalence of restriction from 22.6% (95% CI, 21.5%-23.6%) to 18.0% (95% CI, 17.0%-19.0%), a decrease in the prevalence of a nonspecific pattern of impairment from 8.7% (95% CI, 7.9%-9.4%) to 4.0% (95% CI, 3.5%-4.5%), and no significant change in the percentage with obstruction from 23.9% (95% CI, 22.8%-25.1%) to 25.1% (95% CI, 23.9%- 26.2%). The race-neutral reference equations were associated with an increase in severity in 22.8% (95% CI, 21.2%-24.4%) of Black individuals and a decrease in severity in 19.3% (95% CI, 18.2%-20.3%) of White individuals vs the race-specific reference equations. Conclusions and Relevance: In this cross-sectional study, the use of race-neutral reference equations to interpret PFTs resulted in a significant increase in the number of Black individuals with respiratory impairments along with a significant increase in the severity of the identified impairments. More work is needed to quantify the effect these reference equations would have on diagnosis, referral, and treatment patterns.

Estimating the minimum sample size for interventional and observational studies using the lung clearance index as an endpoint✰.

BACKGROUND: With the increasing availability of highly effective modulators for people living with cystic fibrosis (CF), there is a need to re-design research studies to reflect the changing epidemiology of the CF population. The lung clearance index (LCI), a sensitive physiological measure of lung function, may be ideally suited as an endpoint in the era of CF modulator therapies. In this study we describe study design considerations for implementing LCI into interventional and observational research. METHODS: Simulations were used to estimate the required sample size to detect a range of treatment effects for interventional studies (including cross-over trials) and to track lung disease progression in observational studies. RESULTS: Using published treatment effects to inform the design of prospective studies can lead to inefficient study designs. Large improvements in LCI for a few individuals can skew results and can influence interpretations of treatment effects. Adjusting for baseline LCI can help to improve the efficiency of a study. Compared to the forced expiratory volume in 1 second (FEV1), analysis using LCI as an endpoint requires as little as one third of the total sample size. CONCLUSIONS: Planning of prospective studies that include LCI as an endpoint need to consider baseline LCI and disease severity of the study population; whereas interpretation of results needs to consider whether a few individuals skew the overall treatment effect.

A Race-neutral Approach to the Interpretation of Lung Function Measurements.

Rationale: The use of self-reported race and ethnicity to interpret lung function measurements has historically assumed that the observed differences in lung function between racial and ethnic groups were because of thoracic cavity size differences relative to standing height. Very few studies have considered the influence of environmental and social determinants on pulmonary function. Consequently, the use of race and ethnicity-specific reference equations may further marginalize disadvantaged populations. Objectives: To develop a race-neutral reference equation for spirometry interpretation. Methods: National Health and Nutrition Examination Survey (NHANES) III data (n = 6,984) were reanalyzed with sitting height and the Cormic index to investigate whether body proportions were better predictors of lung function than race and ethnicity. Furthermore, the original GLI (Global Lung Function Initiative) data (n = 74,185) were reanalyzed with inverse-probability weights to create race-neutral GLI global (2022) equations. Measurements and Main Results: The inclusion of sitting height slightly improved the statistical precision of reference equations compared with using standing height alone but did not explain observed differences in spirometry between the NHANES III race and ethnic groups. GLI global (2022) equations, which do not require the selection of race and ethnicity, had a similar fit to the GLI 2012 "other" equations and wider limits of normal. Conclusions: The use of a single global spirometry equation reflects the wide range of lung function observed within and between populations. Given the inherent limitations of any reference equation, the use of GLI global equations to interpret spirometry requires careful consideration of an individual's symptoms and medical history when used to make clinical, employment, and insurance decisions.

Trajectories of early growth and subsequent lung function in cystic fibrosis: An observational study using UK and Canadian registry data.

BACKGROUND: Understanding the pulmonary impact of changes in early life nutritional status over time in a paediatric CF population may help inform how to use nutritional assessment to guide clinical care. National registry data provides an opportunity to study patterns of weight gain over time at the level of the individual, and thus to gain detailed understanding of the relationship between early weight trajectories and later lung function in children with Cystic Fibrosis (CF). METHODS: Using data from the United Kingdom (UK) and Canadian CF Registries, a mixed effects linear regression model was used to describe children's weight and BMI z-score trajectories from age 1 to 5 years. The intercept (weight-for-age at age 1) and slope (weight-for-age trajectory) from this model were then used as covariates in a linear regression of first lung function measurement at age 6 years. RESULTS: In both the UK and Canadian data, greater weight-for-age z-score at age 1 year and greater change in weight-for-age over time were associated with higher FEV1% predicted. A greater weight-for-age z-score at age 1 year was associated with a higher FEV1% predicted (UK: 3.78% (95% CI: 1.76; 4.70); Canada: 3.20% (95%CI: 1.76, 4.70)). These associations were reproduced for BMI z-scores and FVC% predicted. CONCLUSIONS: Early weight-for-age, specifically at age 1 year, and weight-for-age trajectories across early childhood are associated with later lung function. This relationship persists after adjustment for potential confounders. Current guidelines may need to be updated to place less emphasis on a specific cut-off (such as the 10th percentile) and encourage tracking of weight-for-age over time.

The Contribution of Anthropometry and Socioeconomic Status to Racial Differences in Measures of Lung Function: A Systematic Review.

BACKGROUND: The current approach to interpretation of lung function measurements assumes that differences in lung function between racial and ethnic groups represent inherent and biological differences. Observed differences in lung function between White and Black populations are often attributed to physiological differences in body proportions (eg, chest size, leg length); however, most studies investigating the observed differences have not considered the impact of socioeconomic status (SES). RESEARCH QUESTION: What proportion of the differences in lung function between Black and White populations can be attributed to SES and/or differences in body proportions? STUDY DESIGN AND METHODS: PubMed and EMBASE were searched up to March 2022 for articles relating to Black race, SES, and lung function. A total of 4,673 titles and abstracts were screened, followed by assessment for extractable data; 11 articles were ultimately included in this systematic review. RESULTS: There is substantial heterogeneity in the contribution of SES and body proportions to the observed differences in lung function between Black and White individuals. The proportion of differences between Black and White study participants attributable to SES factors ranged from 2.2% to 43.3% in FEV1 and from 4.1% to 41.9% for FVC. Studies that adjusted for sitting height explained 3% to 31.7% of the racial difference in lung function. INTERPRETATION: Reproducible research aimed at explaining the etiology of the differences in lung function between populations is difficult to achieve. The evidence to support the use of race/ethnic specific equations is limited, and the practice needs to be re-evaluated.

Multiple breath washout: measuring early manifestations of lung pathology.

The multiple breath washout (MBW) test measures the efficiency of gas mixing in the lungs and has gained significant interest over the past 20 years. MBW outcomes detect early lung function impairment and peripheral airway pathology, through its main outcome measure lung clearance index (LCI). LCI measures the number of lung turnovers required to washout an inert tracer gas. MBW is performed during normal (tidal) breathing, making it particularly suitable for young children or those who have trouble performing forced manoeuvres. Additionally, research in chronic respiratory disease populations has shown that MBW can detect acute clinically relevant changes before conventional lung function tests, such as spirometry, thus enabling early intervention. The development of technical standards for MBW and commercial devices have allowed MBW to be implemented in clinical research and potentially routine clinical practice. Although studies have summarised clinimetric properties of MBW indices, additional research is required to establish the clinical utility of MBW and, if possible, shorten testing time. Sensitive, feasible measures of early lung function decline will play an important role in early intervention for people living with respiratory diseases. EDUCATIONAL AIM: To describe the multiple breath washout test, its applications to lung pathology and respiratory disease, as well as directions for future research.