The persistent mismeasure of spirometry in women
Authors: Philippe Haouzi, Johnathan McCully
Journal: The Lancet Respiratory Medicine (2024)

The measurements of FEV1, forced vital capacity (FVC), and their ratio are routinely performed in millions of patients every year to diagnose and follow up obstructive and restrictive pulmonary diseases. FEV1 and FVC measurements are compared with two reference values, ie, the mean predicted values and the 5th percentile (lower limit of normal).1Stanojevic S Kaminsky DA Miller MR et al.ERS/ATS technical standard on interpretive strategies for routine lung function tests.Eur Respir J. 2022; 602101499Google Scholar These predicted values are obtained from regression equations, different in men and women, which are computed from the largest available population of healthy individuals that have been accumulated by the Global Lung Function Initiative (GLI) and are a function of age and height.2Cooper BG Stocks J Hall GL et al.The Global Lung Function Initiative (GLI) Network: bringing the world's respiratory reference values together.Breathe (Sheff). 2017; 13: e56-64Crossref PubMed Scopus (123) Google Scholar According to the 2012 GLI regression equations,3Quanjer PH Stanojevic S Cole TJ et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Crossref PubMed Scopus (3962) Google Scholar, 4Quanjer PH Stanojevic S Cole TJ Stocks J Implementing GLI-2012 regression equations.https://www.ers-education.org/lr/show-details/?idP=138979Date: 2015Date accessed: March 25, 2024Google Scholar and until earlier this year, a correction factor, dependent on the race with which a patient would self-identify, was applied to these equations. Five groups were defined: White, Black or African American, northeast Asian, southeast Asian, and others. The correction factor consisted of a negative offset in the Black and southeast Asian groups;3Quanjer PH Stanojevic S Cole TJ et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Crossref PubMed Scopus (3962) Google Scholar, 4Quanjer PH Stanojevic S Cole TJ Stocks J Implementing GLI-2012 regression equations.https://www.ers-education.org/lr/show-details/?idP=138979Date: 2015Date accessed: March 25, 2024Google Scholar as a result the predicted FVC or FEV1 values would be approximately 15% lower in these groups than in White or northeast Asian patients at any given age and height, both in men and women.4Quanjer PH Stanojevic S Cole TJ Stocks J Implementing GLI-2012 regression equations.https://www.ers-education.org/lr/show-details/?idP=138979Date: 2015Date accessed: March 25, 2024Google Scholar As a consequence, predefined categories based on self-identified ethnical or geographical criteria or the superficial appearance of race have led us to consider lower predicted FEV1 and FVC as the norm in many patients when compared with the White group, with clinical consequences for the diagnosis and follow-up of various respiratory diseases.2Cooper BG Stocks J Hall GL et al.The Global Lung Function Initiative (GLI) Network: bringing the world's respiratory reference values together.Breathe (Sheff). 2017; 13: e56-64Crossref PubMed Scopus (123) Google Scholar, 5Bhakta NR Bime C Kaminsky DA et al.Race and ethnicity in pulmonary function test interpretation: an official American Thoracic Society statement.Am J Respir Crit Care Med. 2023; 207: 978-995Crossref PubMed Scopus (44) Google Scholar, 6Sitarik AR Wegienka G Johnson CC Joseph CLM Impact of spirometry race-correction on preadolescent Black and White children.J Allergy Clin Immunol Pract. 2023; 11: 3097-3106Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 7Moffett AT Bowerman C Stanojevic S Eneanya ND Halpern SD Weissman GE Global, race-neutral reference equations and pulmonary function test interpretation.JAMA Netw Open. 2023; 6e2316174Crossref Scopus (6) Google Scholar, 8Colon Hidalgo D Ramos KJ Harlan EA et al.Historic use of race-based spirometry values lowered transplant priority for Black patients.Chest. 2023; 165: 381-388Summary Full Text Full Text PDF Scopus (0) Google Scholar Many criticisms were voiced against the clinical relevance of such categories5Bhakta NR Bime C Kaminsky DA et al.Race and ethnicity in pulmonary function test interpretation: an official American Thoracic Society statement.Am J Respir Crit Care Med. 2023; 207: 978-995Crossref PubMed Scopus (44) Google Scholar and a 2023 statement from the American Thoracic Society,5Bhakta NR Bime C Kaminsky DA et al.Race and ethnicity in pulmonary function test interpretation: an official American Thoracic Society statement.Am J Respir Crit Care Med. 2023; 207: 978-995Crossref PubMed Scopus (44) Google Scholar endorsed by the European Respiratory Society, recommended to abandon the corrections related to race and use a race-neutral approach to spirometry by using average reference equations. New race-neutral weighted average equations, which are functions of age and height only, are now used for FEV1 and FVC; one equation for men and one for women.9Bowerman C Bhakta NR Brazzale D et al.A race-neutral approach to the interpretation of lung function measurements.Am J Respir Crit Care Med. 2023; 207: 768-774Crossref PubMed Scopus (35) Google Scholar Individuals who self-identify as White have a modestly lower mean and lower limit of normal predicted values than before 2023, whereas those who self-identify as Black or southeast Asian have higher predicted values.3Quanjer PH Stanojevic S Cole TJ et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Crossref PubMed Scopus (3962) Google Scholar, 4Quanjer PH Stanojevic S Cole TJ Stocks J Implementing GLI-2012 regression equations.https://www.ers-education.org/lr/show-details/?idP=138979Date: 2015Date accessed: March 25, 2024Google Scholar, 9Bowerman C Bhakta NR Brazzale D et al.A race-neutral approach to the interpretation of lung function measurements.Am J Respir Crit Care Med. 2023; 207: 768-774Crossref PubMed Scopus (35) Google Scholar Yet, women still have substantially lower predicted values than men, by 10–20% (figure), a difference that increases with age. One must recognise that, the difference between predicted values in men and women has not fundamentally changed over the past 25 years.5Bhakta NR Bime C Kaminsky DA et al.Race and ethnicity in pulmonary function test interpretation: an official American Thoracic Society statement.Am J Respir Crit Care Med. 2023; 207: 978-995Crossref PubMed Scopus (44) Google Scholar, 10Hankinson JL Odencrantz JR Fedan KB Spirometric reference values from a sample of the general US population.Am J Respir Crit Care Med. 1999; 159: 179-187Crossref PubMed Google Scholar The point developed in this Correspondence is that maintaining lower predicted values for women than for men might not be justified. Indeed, the rationale used to justify maintaining a lower FEV1 or FVC for women relies on various anatomical and physiological considerations11LoMauro A Aliverti A Sex differences in respiratory function.Breathe (Sheff). 2018; 14: 131-140Crossref PubMed Scopus (0) Google Scholar supporting a difference in the mechanics and dynamic of the chest wall, the position of the ribs and the diaphragm,12García-Martínez D Torres-Tamayo N Torres-Sanchez I García-Río F Bastir M Morphological and functional implications of sexual dimorphism in the human skeletal thorax.Am J Phys Anthropol. 2016; 161: 467-477Crossref PubMed Scopus (0) Google Scholar and in dysanapsis. It is not known whether these differences in anatomy still hold when larger populations of subjects are studied and whether they translate into clinically relevant differences in pulmonary function. Second, when 2012 GLI regressions were used, predicted values were lower in women than in men of the same race. Still, the predicted values in White women were undistinguishable from those established for the Black or southeast Asian men4Quanjer PH Stanojevic S Cole TJ Stocks J Implementing GLI-2012 regression equations.https://www.ers-education.org/lr/show-details/?idP=138979Date: 2015Date accessed: March 25, 2024Google Scholar (figure), an observation that has been overlooked when changing to race neutral equations. The new race-neutral regression equations have increased predicted values in Black and southeast Asian men by 8–16%, which are now the same for all men; in contrast, predicted absolute values have decreased by 5% in White women younger than 55 years, while they have modestly increased by a few percent after age 70 years (figure). The exact same observation can be made when comparing northeast Asian women to Black men or northeast Asian men and White women to southeast Asian men. Scientifically and ethically justifying why populations with the same initial predicted values should be treated differently might seem difficult. Finally, the study of the frequency distribution of FEV1 and FVC in women and men based on the published coefficient of variation, skewness, and lower limit of normal of FEV1 and FVC9Bowerman C Bhakta NR Brazzale D et al.A race-neutral approach to the interpretation of lung function measurements.Am J Respir Crit Care Med. 2023; 207: 768-774Crossref PubMed Scopus (35) Google Scholar shows that 88% and 79% of all women studied in the 2023 GLI cohort were higher than the lower limit of normal for all men for FEV1 and FVC respectively (figure). In addition, about 20% of women have displayed mean predicted values that are higher than in men. In other words, in the absence of lung diseases, FEV1 and FVC are in many women higher than the lower limit of normal used for men of the same age and height. If sex-specific reference equations were abandoned, predicted values would be higher in women than with the current equations; however, the clinical impact of such a change remains unclear. When ethnicity (2012 GLI) was considered, African American patients were found to have a more limited access to lung transplants than White patients,8Colon Hidalgo D Ramos KJ Harlan EA et al.Historic use of race-based spirometry values lowered transplant priority for Black patients.Chest. 2023; 165: 381-388Summary Full Text Full Text PDF Scopus (0) Google Scholar due to lower predicted values. The same must have happened to all women. Conversely, would high-risk procedures, such as lung or cardiac surgery, be more often denied in women, if cut-off values were increased by more than 20%? The net clinical effect of abandoning the lower predicted and lower limit of normal values in women than in men must therefore be evaluated, with a specific focus on the oldest patients (figure). Whether reference values according to sex should be abandoned, maintained, or modified, in keeping with a fair evaluation of the impact, could prove to be difficult to establish. We could propose that, in the absence of a clear answer, too strict cut-offs for medical or surgical decisions in women should be avoided and, when in doubt, higher predicted values could be used for women if pulmonary function results are the only factor preventing the prescription of a treatment or offering an otherwise obvious diagnosis. As new race neutral predicted and lower limit of normal values have been implemented, it is time to revisit our rationale and the clinical effects for using different predicted spirometry values in women and men. We declare no competing interests.