INTRODUCTION — Correct interpretation of pulmonary function tests (PFTs) requires the use of appropriate reference values to which the patient's results are compared [1-4].
Unlike many physiologic parameters, for which normal values do not vary with the characteristics of the particular patient, predicted values of pulmonary function depend upon age, sex, and height. Normal values appear to also vary with the patient's race or ethnic background, but the role played by ancestry and/or environmental and social determinants of health is unclear. Therefore, interpretation of PFTs performed for the first time must take these and other factors into consideration. In practice, spirometers and pulmonary function test equipment have software that uses reference equations for calculation of "predicted values," as determined by published studies of large numbers of healthy individuals [3,4].
The American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on the standardization of spirometry, as well as other ATS guidelines, can be accessed through the ATS web site at www.thoracic.org/statements.
The effects of age, sex, and height on the determination of normal predicted values for interpretation of PFTs, and the use of different predicted reference sets, are reviewed here. We also comment on the effects of weight and race/ethnicity. Finally, we discuss using statistical approaches to define normality. The technique and interpretation of PFTs are discussed separately. (See "Office spirometry" and "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in children" and "Diffusing capacity for carbon monoxide".)
EFFECT OF AGE, SEX, HEIGHT, AND WEIGHT — PFT results are dependent upon age, sex, and height. Although weight is not a determining factor of lung size or function, body weight may influence lung function results.
Age and sex
Childhood — During childhood up until puberty, lung function increases linearly in proportion to overall growth, which is determined at least in part by age and sex [5,6]. The growth spurt associated with early adolescence is associated with an increase in the rate of overall growth and the rate of increase in lung volumes (and maximal flows) and occurs at slightly different ages in girls and boys (figure 1A and figure 1B).
On average, girls reach both their maximal height and their maximal lung volume earlier than boys, but boys achieve larger lung volumes.
In children, the normal growth of lung function is fast when compared to the rate of changes observed with disease or therapy. As a result, the use of growth charts (looking for trends across percentile lines) most accurately reflects changes that cannot be attributed to growth (figure 1A-B).
Adulthood — Cross-sectional spirometric testing of large healthy populations shows a plateau of lung function between the ages of 20 and 30 (figure 2A-B). However, longitudinal observation of individuals shows that some have a lung function peak in their early 20s, while others, particularly men, may have the peak in their mid-30s [7].
Healthy nonsmokers without exposure to air pollution experience a gradual decline in lung function throughout adulthood and old age:
●The forced expiratory volume in one second (FEV1) decreases approximately 20 to 30 mL per year [8,9]
●The vital capacity (VC) decreases while the residual volume (RV) increases, leaving the total lung capacity intact
●The diffusing capacity for carbon monoxide (DLCO, also known as transfer factor) declines linearly with age
Among adults, even though gender identify must be respected, sex at birth (through puberty) should be used to assess predicted values of lung function [10].
Height — Taller persons have a larger frame size and a larger thoracic cage than do shorter persons. Consequently, taller persons have:
●Larger lung volumes
●Higher maximal flow rates
●A greater ability to take up oxygen and carbon monoxide per minute (reflected by a higher diffusing capacity for carbon monoxide [DLCO])
As an example, the predicted (mean) vital capacity of a 40 year old man who is 6 feet 4 inches (193 cm) is six liters, while that of a man who is a foot shorter at 5 feet 4 inches (163 cm) is four liters. Therefore, the accurate measurement, preferably with a stadiometer, of standing height (to the nearest half inch or cm, without shoes) is very important in predicting lung function for a particular patient [3]. Technicians should not rely on the stated height.
Weight — Body weight is much less important than standing height when predicting most pulmonary function values; as a result, weight is not included in spirometry prediction equations. However, extremes in weight are associated with changes in lung volumes [11-16]. The body mass index (BMI), which is obtained by dividing the weight (in kilograms) by the square of the height (in meters) (calculator 1), can be used to quantify obesity.
The most consistent effect of obesity is reduction in FRC and expiratory reserve volume (ERV) (figure 3) [15,16]. Mildly reduced lung volumes in patients with a BMI above 30 kg/m2 may be entirely due to obesity [14]. Further increases in BMI above 30 kg/m2 result in additional decreases in FRC and ERV [16]. The effect on spirometry tends to be small. FEV1 and FVC may be slightly reduced and the ratio is usually preserved, particularly in adults. (See "Overview of pulmonary function testing in adults", section on 'Lung volumes'.)
EFFECT OF RACE/ETHNICITY — Lung function may vary among people from different racial or ethnic backgrounds. In order to define these differences, large datasets have been developed by measuring lung function (specifically spirometry) in a broad range of healthy individuals both in the United States (NHANES 3 dataset) and across the world, including the United States (GLI 2012 dataset) (see 'Spirometry' below). Healthy individuals are defined by being a never smoker and having no pulmonary symptoms or known lung disease. The NHANES 3 and GLI 2012 reference equations, which include race and ethnicity, represent the best evidence for defining normal spirometry values in the populations studied.
The approach to evaluating the influence of race and ethnicity on lung function is complex [17]. For example, patients may be of mixed heritage and may not always know their exact racial/ethnic background [18]. Furthermore, the degree to which lung function varies as a consequence of complex socioeconomic, nutritional, and environmental factors, in addition to possible genetic ancestry, is not known [17,19,20]. Thus, using normative values from healthy individuals of the same race or ethnic background as the patient is the best evidence-based method to interpret a patient's lung function. So-called "correction factors" to adjust non-White values are not recommended. Using one set of normative values for all people may ultimately be appropriate, but further research is necessary to ensure that such an approach does not have unintended adverse consequences for diagnosis, clinical decision-making, and patient care.
While differences in absolute values of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), lung volumes, diffusing capacity for carbon monoxide (DLCO), and maximal inspiratory and expiratory pressures (MIP and MEP) have been described for different race/ethnic groups, ratios such as FEV1/FVC and residual volume (RV)/total lung capacity (TLC) appear to be relatively independent of a patient's background.
PULMONARY FUNCTION REFERENCE EQUATIONS — Reference equations should be selected to best represent the characteristics of the patients being tested in a given laboratory. Reference equations should not be used (extrapolated) for patients whose age or height is outside the range of subjects included in the reference study. The reference equations that are being used to create predicted values should be included in the pulmonary function report, as outlined in the “Recommendations for a Standardized Pulmonary Function Report” [21].
Spirometry — Large reference studies for spirometry have been performed in healthy subjects in Europe and North America [2-4]. These studies, National Health and Nutrition Examination Survey (NHANES) III and Global Lung Function Initiative (GLI), have been used to generate reference equations for use in analyzing spirometry results, although additional data are needed for individuals under age 3 and over age 95.
●Global Lung Function Initiative – In 2012, the Global Lung Function Initiative (GLI) published spirometric prediction equations for ages 3 to 95 years for ethnic and geographic groups in 26 countries comprising White American, White European, African American, North Asian, and Southeast Asian individuals. These reference equations are endorsed by the European Respiratory Society, American Thoracic Society, American College of Chest Physicians, the Australian and New Zealand Society of Respiratory Science, Thoracic Society of Australia and New Zealand, and Asian Pacific Society for Respirology. The GLI reference equations are recommended for use in North America, as well as in Europe and Australia-New Zealand [21].
Reference data are needed for other population groups, particularly Arab, Indian, Polynesian, African, and Latin American, and also ethnic minorities [4]. In the meantime, though not perfect, a composite equation labeled "Other" is provided for those not represented in these groups or of mixed racial/ethnic origin.
●NHANES III – In 2005, the American Thoracic Society (ATS)-European Respiratory Society Task Force published a listing of pulmonary function reference values and recommendations for interpretative strategies [3]. For the United States, race/ethnically appropriate National Health and Nutrition Examination Survey (NHANES) III reference equations were recommended for spirometry for those 8 to 80 years old [2]. Specific recommendations were not made for use in Europe at that time. A separate set of equations were recommended for those under eight years [5] but, subsequently, reference equations that can be applied across the spectrum of ages spanning childhood and adulthood were published [6]. For laboratories that are using NHANES III reference equations and choose to maintain continuity, simulation study has demonstrated that GLI and NHANES III are generally concordant with the most notable difference among those at the extremes of height and age [22].
Criteria for selecting pulmonary function reference equations include the following [3]:
●A population sample (with a wide range of age and height) is preferred to a convenience sample (eg, using volunteers or patients referred to a clinic).
●All subjects should be never smokers.
●Subjects should be free of heart disease, lung disease, and chronic respiratory symptoms.
●The spirometers and test methods should meet current ATS/ERS recommendations. Almost all studies performed prior to 1981 did not conform to ATS standards.
Refinement of reference equations may be needed for patients of certain backgrounds. As an example, use of background-specific reference equations may be more accurate for patients in the United States who are of Dominican or Puerto Rican background [23]. In the Hispanic Community Health Study/Study of Latinos (16,415 participants, aged 18 to 74 years), those of Dominican or Puerto Rican background had lower predicted and lower limit of normal values for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), than those of other Hispanic/Latino or Mexican American background.
Diffusing capacity for carbon monoxide (DLCO) — In 2017, the GLI published prediction equations for DLCO, also known as carbon monoxide transfer factor (TLCO) in Europe and other areas of the world. These reference equations apply to White populations who are age 5 to 85 years. The equations are based on data from over 12,000 individuals in 14 countries and 85 percent of the data were from White populations.
The GLI reference equations provide normative values based on a large, internationally representative dataset and expand on the previously existing reference equations that were based on smaller populations [3,24-31]. The GLI plans to validate these reference values in broader populations in future studies. The GLI reference equations for DLCO have been endorsed by the ATS, ERS, American College of Chest Physicians, and the Asian Pacific Society of Respirology.
Other pulmonary function tests — Reference values for lung volumes (eg, total lung capacity [TLC], residual volume [RV], and functional residual capacity [FRC]) have been derived from much smaller patient populations compared with spirometry or DLCO reference standards [3,32-35]. The GLI plans to publish reference equations for lung volumes soon.
Reference values for maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in older adults have also been published [36]. These studies have been limited to a narrower age range and therefore may have limitations in applicability [32].
Reference values for the six-minute walk distance for adults were published in 1998; this was followed by an ATS guideline on the subject in 2002 [37,38], which was updated by ATS/ERS in 2014 [39]. Sex, age, height, and weight must all be considered when interpreting this test [39]. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)
UPPER AND LOWER LIMITS OF NORMALITY — In the 2005 guidelines, the American Thoracic Society and European Respiratory Society recommended that the fifth percentile be used as the lower limit of the normal range (LLN). By definition, only 5 percent of healthy individuals will have a result below this LLN. Note that the 5th percentile occurs at 1.64 standard deviations below the mean, defining a "z-score" of -1.64. Thus, any low value can be remembered easily by having a z-score of less than -1.64.
Prior to this, a traditional rule of thumb was to use 80 percent of predicted as the LLN for most pulmonary function test results. This standard works fairly well for forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity for carbon monoxide (DLCO), and total lung capacity (TLC) in middle-aged adults, but gives a high rate of false positive or false negatives for FEV1/FVC, forced expiratory flow (FEF, also called maximum midexpiratory flow) 25 to 75 percent, and maximal respiratory pressures, especially when used for adolescents and adults over the age of 60 [40].
The use of the LLN rather than a fixed ratio cut off (eg FEV1/FVC 0.7) to define airflow obstruction reduces the misclassification that occurs with a fixed ratio approach. The fixed ratio tends to under-diagnose younger individuals and over-diagnose older individuals with airflow obstruction and the LLN incorporates the changes in FEV1/FVC that occur with age and therefore, reduces this misclassification. Categorizing results as "borderline" abnormal if they fall near the LLN is also a useful concept. (See "Office spirometry", section on 'Ratio of FEV1/FVC'.)
Of note, use of the LLN to define normal is controversial [41], as some argue that normality should be defined by clinical and not statistical criteria [42], and either the fixed ratio or the LLN may variably correlate better with clinical outcomes [43].
Static lung volumes and DLCO values are also abnormal when values are above or below a reference standard, so that the normal range for these studies should include both an upper limit of normal (ULN) and an LLN.
Even when age, sex, height, and race/ethnicity are taken into consideration, the "normal" range for measurements of pulmonary function remains wide. This means that large changes with disease progression or therapy can easily occur while the patient's values remain within the normal range. Therefore, follow-up pulmonary function tests in adults should be compared with the patient's previous (baseline) values, not the predicted values.
ENVIRONMENTAL INFLUENCES — Exposure to indoor air pollution, including passive and active exposure to cigarette smoke, and outdoor air pollution can affect lung growth and function. As an example, early childhood exposure to parental smoking is associated with reduced lung function in school age children [44]. All cigarette smoking (starting during the early teens) is associated with an earlier peak in lung function and therefore an earlier onset of decline [7]. In addition, all of the changes due to aging are accelerated in susceptible cigarette smokers.
Childhood exposure to air pollution has been associated with reduced pulmonary function in a number of studies [45-50]. It is thought that children are particularly susceptible to the effects of poor air quality as lung development continues during childhood [51] and because the higher ventilatory rate and greater likelihood of outdoor exercise result in increased exposure [45]. Both restrictive and obstructive defects have been identified. One cohort study did not find a correlation between air pollution exposure and lung function, but the exposure models used may not have included adjustments for changes in exposure over time [52].
Other factors related to the social environment, such as socioeconomic status [53] and pre- and perinatal nutrition [54], may influence lung development and health.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary function testing".)
SUMMARY AND RECOMMENDATIONS
●During childhood up until puberty, lung function increases linearly in proportion to overall growth, which is determined at least in part by age and sex. Healthy never-smoking adults without exposure to air pollution experience a gradual decline in lung function. The forced expiratory volume in one second (FEV1) decreases approximately 30 mL per year. The vital capacity decreases while the residual volume increases, leaving the total lung capacity intact. The diffusing capacity for carbon monoxide (DLCO) declines linearly with age. (See 'Effect of age, sex, height, and weight' above.)
●Correct interpretation of pulmonary function tests (PFTs) requires comparison of the patient's values with appropriate reference values. The majority of spirometers and pulmonary function equipment use software with reference equations to generate predicted values for each patient. (See 'Introduction' above and 'Pulmonary function reference equations' above.)
●Reference equations should be listed on the pulmonary function testing report as recommended by the ATS statement on Recommendations for a Standardized Pulmonary Function Report. (See 'Pulmonary function reference equations' above.)
●Predicted values should be obtained from studies of healthy persons of the same age, sex, height, and racial/ethnic background as the patient being tested. Reference equations should not be used (extrapolated) for patients whose age or height is outside the range of subjects included in the reference study. (See 'Pulmonary function reference equations' above.)
●The Global Lung Function Initiative (GLI) reference standards for spirometry are based on data from large, internationally representative populations and are recommended for use in North America, Europe, and Australia-New Zealand. The NHANES III reference standards for spirometry are used for continuity over time in many labs in North America. Differences between GLI and NHANES III are most notable at the extremes of height and age. (See 'Spirometry' above.)
●The GLI reference equations for DLCO are based on large internationally representative data and provide reference values for White populations from ages 5 to 85 years [55]. (See 'Diffusing capacity for carbon monoxide (DLCO)' above.)
●Reference standards for static lung volumes and capacities (eg, total lung capacity, residual volume, and functional residual capacity (figure 3)) are based on smaller populations than those for spirometry or DLCO, but GLI reference values are expected soon. (See 'Other pulmonary function tests' above.)
●Body weight is much less important than height when predicting most pulmonary function values and is not included in reference equations for spirometry. However, patients with a body mass index (BMI) above 30 kg/m2 may have mildly reduced lung volumes. (See 'Weight' above.)
●Airway obstruction should be determined by a forced vital capacity/forced expiratory volume in one second (FEV1/FVC) ratio below the age and sex-specific lower limit of normal (LLN), determined from the fifth percentile. The use of other indices (eg, 0.7) increases the misclassification rates above the accepted 5 percent level. The LLN can also be used for the interpretation of FVC, and forced expiratory volume in one second FEV1. (See 'Upper and lower limits of normality' above.)
●Static lung volumes and DLCO values are abnormal when values are above or below a reference standard, so that the normal range for these studies should include both an upper limit of normal (ULN) and LLN, determined by the upper and lower fifth percentiles. This approach should replace the traditional rule of thumb of using 80 and 120 percent of predicted as the LLN and ULN for most pulmonary function test values. (See 'Upper and lower limits of normality' above.)
●Even when age, height, sex, and race/ethnicity are taken into consideration, the "normal" range for measurements of pulmonary function remains wide. It is, therefore, important to compare absolute values in lung function parameters when assessing change over time in a given individual. (See 'Upper and lower limits of normality' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Enright, MD, who contributed to an earlier version of this topic review.
1 : Standardisation of spirometry.
2 : Spirometric reference values from a sample of the general U.S. population.
3 : Interpretative strategies for lung function tests.
4 : Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
5 : Pulmonary function between 6 and 18 years of age.
6 : Reference ranges for spirometry across all ages: a new approach.
7 : Lung function development in young adults: is there a plateau phase?
8 : Decline of FEV1 by age and smoking status: facts, figures, and fallacies.
9 : The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort.
10 : The Impact of Using Non-Birth Sex on the Interpretation of Spirometry Data in Subjects With Air-Flow Obstruction.
11 : Fat distribution and end-expiratory lung volume in lean and obese men and women.
12 : Altered resting and exercise respiratory physiology in obesity.
13 : Altered respiratory physiology in obesity.
14 : The effect of adiposity measured by dual-energy X-ray absorptiometry on lung function.
15 : Physiology of obesity and effects on lung function.
16 : The effects of body mass index on lung volumes.
17 : Rethinking the Race Adjustment in Pulmonary Function Testing.
18 : "Race correction" in pulmonary-function testing.
19 : Effects of nutrition, growth hormone disturbances, training, altitude and sleep on lung volumes.
20 : Genetic ancestry in lung-function predictions.
21 : Recommendations for a Standardized Pulmonary Function Report. An Official American Thoracic Society Technical Statement.
22 : Comparison of NHANES III and ERS/GLI 12 for airway obstruction classification and severity.
23 : Spirometry Reference Equations from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos).
24 : The single-breath carbon monoxide diffusing capacity. Reference equations derived from a healthy nonsmoking population and effects of hematocrit.
25 : Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state. Predicted values, lower limits of normal, and frequencies of abnormality by smoking history.
26 : Standardized single breath normal values for carbon monoxide diffusing capacity.
27 : Reference equations for the single-breath diffusing capacity. A cross-sectional analysis and effect of body size and age.
28 : Single-breath carbon monoxide diffusing capacity prediction equations from a Mediterranean population.
29 : Single-breath carbon monoxide diffusing capacity prediction equations from a Mediterranean population.
30 : Prediction equations for single breath diffusing capacity (Tlco) in a middle aged caucasian population.
31 : 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung.
32 : Lung volume reference values for women and men 65 to 85 years of age.
33 : Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on Lung Volume Measurements. Official Statement of The European Respiratory Society.
34 : Lung volumes and forced ventilatory flows.
35 : Lung volumes in 4,774 patients with obstructive lung disease.
36 : Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group.
37 : Reference equations for the six-minute walk in healthy adults.
38 : ATS statement: guidelines for the six-minute walk test.
39 : An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease.
40 : Underestimation of airflow obstruction among young adults using FEV1/FVC<70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes.
41 : The lower limit of normal versus a fixed ratio to assess airflow limitation: will the debate ever end?
42 : Should we be using statistics to define disease?
43 : Assessment of comorbidities and prognosis in patients with COPD diagnosed with the fixed ratio and the lower limit of normal: a systematic review and meta-analysis.
44 : The effects of tobacco smoke exposure on respiratory health in school-aged children.
45 : Air Pollution Levels and Children's Lung Health. How Low Do We Need to Go?
46 : Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children's Health Study.
47 : Panel studies of air pollution on children's lung function and respiratory symptoms: a literature review.
48 : Lifetime Exposure to Ambient Pollution and Lung Function in Children.
49 : Exposure to industrial air pollutant emissions and lung function in children: Canadian Health Measures Survey, 2007 to 2011.
50 : Associations of children's lung function with ambient air pollution: joint effects of regional and near-roadway pollutants.
51 : The effect of air pollution on lung development from 10 to 18 years of age.
52 : Long-term air pollution exposure and lung function in 15 year-old adolescents living in an urban and rural area in Germany: The GINIplus and LISAplus cohorts.
53 : Socioeconomic status and pulmonary function, transition from childhood to adulthood: cross-sectional results from the polish part of the HAPIEE study.
54 : Trajectories of Lung Function in Infants and Children: Setting a Course for Lifelong Lung Health.
55 : Official ERS technical standards: Global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians.
