Association of forced expiratory volume in 0.5 seconds/forced vital capacity ratio with all-cause mortality in adults: a cohort study

Introduction

Chronic respiratory diseases (CRDs) refer to a group of disorders affecting the health of the lungs and airways, including chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, interstitial lung diseases, and sarcoidosis, which collectively impose a substantial global disease burden (1-3). Early diagnosis, clinical management, and prognostic assessment of CRDs necessitate lung function testing. However, current lung function indicators remain insufficient to comprehensively characterize the clinical features and early lesions of CRDs in the general population. Therefore, there is a critical need to identify additional lung function indicators that better reflect long-term respiratory health outcomes at the population level.

In both pediatric and adult populations, the forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ratio is a crucial component in the assessment of respiratory health and has been used as a significant indicator of outcomes in clinical trials (4-7). In recent years, new indices, including FEV₁/forced expiratory volume in 3 seconds (FEV₃), FEV₃/forced expiratory volume in 6 seconds (FEV₆), FEV₁/FEV₆, and forced expiratory volume in 0.75 seconds (FEV_0.75)/FVC, have demonstrated their usefulness as part of lung function assessment in different scenarios (8-14). Previous studies have demonstrated the efficacy of the FEV_0.75/FVC and forced expiratory volume in 0.5 seconds (FEV_0.5)/FVC ratios to assess asthma control and wheeze impairment in preschool children (12). However, after a detailed literature search, no studies on the association between the FEV_0.5/FVC ratio and respiratory health prognosis in adults were identified.

An understanding of the association between FEV_0.5/FVC and respiratory health prognosis in adults could inform the design of comprehensive lung function assessments in high-risk populations, thereby improving the overall validity of such assessments. To overcome this gap in knowledge, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) to explore the association between FEV_0.5/FVC and the respiratory health prognosis of adults. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-319/rc).

Methods

Study design and population

Our data were obtained from NHANES, conducted by the National Center for Health Statistics (NCHS) under the U.S. Centers for Disease Control and Prevention (CDC). NHANES is a continuous, nationally representative survey employing a complex, multistage probability sampling design with stratification, clustering, and oversampling of key demographic groups to assess the health and nutritional status of the civilian, non-institutionalized U.S. population. Data collection integrates in-home interviews (demographic, socioeconomic, dietary, and health-related questionnaires) with standardized physical examinations and extensive laboratory testing conducted in mobile examination centers (15-17). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol for the NHANES study was formally approved by the Research Ethics Review Board of NCHS (with the respective protocol numbers #2005-06 and #2011-17) (15-17). Our dataset is sourced from the NHANES website (wwwn.cdc.gov/nchs/nhanes/default.aspx), covering two cycles: 1988–1994 (NHANES III) and 2007–2012. It is primarily based on the availability of lung function measurement data, and these two cycles include comprehensive demographic, examination, and questionnaire data.The detailed enrollment criteria for this study were as follows: (I) age ≥20 years; (II) not pregnant; (III) available and acceptable spirometry data; (IV) FEV_0.5 data; (V) complete demographic and smoking status data; and (VI) complete all-cause mortality follow-up data.

Lung function assessment

The spirometer used to assess pulmonary function in both experimental cycles was the Ohio 822/827 Dry Rolled Volume Sealed Spirometer. The majority of the participants underwent prebronchodilator spirometry, while a minority underwent postbronchodilator spirometry. Accordingly, this study was based on an analysis of the prebronchodilator spirometry data. The testing procedures were in accordance with the recommendations of the American Thoracic Society (ATS) (18). FEV_0.5 and FVC were determined by pulmonary function assessment, and FEV_0.5/FVC ratios were calculated.

The study used rigorous quality control measures to exclude a range of participants who did not meet the criteria for pulmonary function testing. In the NHANES III [1988–1994], individuals lacking reproducible FEV₁ measurements and having at least two acceptable tests were excluded. Individuals who did not achieve a data quality grading of A or B during the 2007–2012 NHANES cycle were excluded in accordance with the ATS data collection criteria. Grade A quality control was defined as exceeding the ATS data collection criteria, which included the presence of three acceptable curves and two reproducible curves, as well as two observations in 100 mL. Grade B quality control was defined as meeting the ATS data collection criteria, which included the presence of three acceptable curves and two reproducible curves, as well as two observations in 150 mL (18,19).

In accordance with the observed trend in the distribution of the overall prebronchodilator FEV_0.5/FVC data, all participants were classified into one of five groups (I–V) based on the FEV_0.5/FVC ratio, as follows—group I, FEV_0.5/FVC ≤0.55; group II, 0.55< FEV_0.5/FVC ≤0.60; group III, 0.60< FEV_0.5/FVC ≤0.65; group IV, 0.65< FEV_0.5/FVC ≤0.70; and group V (reference), FEV_0.5/FVC >0.70.

Outcome

All-cause mortality was the primary outcome. Mortality outcomes were ascertained by probabilistic linkage of NHANES participants to the National Death Index (NDI) using 12 identifiers—including social security number, date of birth, and sex—and verified by death certificates. Follow-up started at the baseline examination and ended on December 31, 2019, with survival time calculated in person-months. All-cause mortality was derived from the NHANES Linked Mortality File, which is maintained by the NCHS.

The secondary outcomes were the risks of comorbidities and chronic respiratory symptoms. We selected eight comorbidities for analysis, including asthma, chronic bronchitis, emphysema, congestive heart failure, stroke, cancer, diabetes mellitus, and hypertension. Information regarding the presence of comorbidities was obtained from the participants using baseline questionnaire at NHANES enrollment. We also gathered data on four chronic respiratory symptoms, including chronic cough, chronic phlegm, wheezing, and dyspnea. Information regarding chronic respiratory symptoms was obtained via baseline patient self-reporting.

Covariate definitions

Data on age, sex, race, body mass index (BMI), and smoking status were procured from the NHANES website. BMI was calculated as weight in kilograms divided by height in meters squared, and the resulting value was categorized as underweight (<18.5 kg/m²), normal (≥18.5 to <25.0 kg/m²), overweight (≥25.0 to <30.0 kg/m²), or obese (≥30.0 kg/m²). The self-identified race of the participants was categorized as Mexican-American, non-Hispanic White, non-Hispanic Black, or other. Smoking status was classified as never smoker, former smoker, or current smoker.

Statistical analysis

Continuous variables were compared by analysis of variance, while categorical variables were compared using the χ² test. The log-rank test and Kaplan-Meier survival analyses were used to evaluate the disparities in mortality risk between the two groups. Univariable and multivariable logistic regression models were used to elucidate the associations of FEV_0.5/FVC with the risk of comorbidities and chronic respiratory symptoms. The trend in the association between FEV_0.5/FVC and the risk of comorbidities and chronic respiratory symptoms was calculated using quartiles as quasi-continuous variables in the multivariable logistic regression model.

Furthermore, univariable and multivariable Cox regression models were used to investigate potential associations between FEV_0.5/FVC and all-cause mortality. The Schoenfeld residual test was used to evaluate the proportional-risk hypothesis through graphical representation. The trend for the association of FEV_0.5/FVC with all-cause mortality was calculated using quartiles as quasi-continuous variables in the multivariable Cox regression model. To better represent the non-linear relationship between lung function and all-cause mortality risk, we conducted a multivariable Cox regression analysis using the five-split restricted cubic spline (RCS) method. RCS enables the identification of risk function inflection points (thresholds). The spline is defined using five nodes, situated at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Thresholds were identified as time points exhibiting a minimal hazard ratio (HR). This analysis divided the subgroups by age (20–40, 41–60, >60 years), sex, race (Mexican-American, non-Hispanic White, non-Hispanic Black, other), BMI (underweight, normal, overweight, obese), and smoking status (never smoker, former smoker, current smoker). Additional analyses were performed to assess the association of FEV_0.5/FVC with all-cause mortality in different subgroups. A bilateral P value <0.05 was considered statistically significant. The analyses were adjusted for five factors: sex, age, BMI, smoking status, and race. The statistical analyses were performed using R, version 4.0.3, and IBM SPSS Statistics, version 29.0.1.0.

Results

Baseline characteristics

Overall, 50,492 subjects were enrolled in the NHANES 1988–1994 and NHANES 2007–2012 (Figure 1). Individuals aged <20 years (n=13,954); pregnant women (n=337); individuals lacking FEV_0.5 data (n=7,733), with unacceptable spirometry results (n=3,016), with no data on smoking status (n=7), and with no data on BMI (n=58); and one individual with unacceptable FEV_0.5 data (n=1) were excluded from the analysis. A total of 25,357 participants who met the inclusion criteria were included.

Figure 1 Flow chart of subject selection for this study. BD, bronchodilator; BMI, body mass index; FEV_0.5, forced expiratory volume in 0.5 seconds; NHANES, National Health and Nutrition Examination Survey.

The mean ± standard deviation age was 46.1±17.2 years, and 48.7% of the participants were male. The mean BMI was 28.0±6.3 kg/m², and the mean FEV_0.5/FVC was 62.5%±8.9% (Table 1). Group I included 4,640 participants, group II included 4,583, group III included 6,135, group IV included 5,744, and group V included 4,255 (Figure 2).

Figure 2 Distribution of forced expiratory volume in 0.5 seconds/forced vital capacity at baseline. Group I, FEV_0.5/FVC ≤0.55; group II, 0.55< FEV_0.5/FVC ≤0.60; group III, 0.60< FEV_0.5/FVC ≤0.65; group IV, 0.65< FEV_0.5/FVC ≤0.70; and group V (reference), FEV_0.5/FVC >0.70. BD, bronchodilator; FEV_0.5, forced expiratory volume in 0.5 seconds; FVC, forced vital capacity; SD, standard deviation.

Associations of FEV_0.5/FVC with comorbidities and chronic respiratory symptoms

The results of the logistic regression analysis of the associations of FEV_0.5/FVC with comorbidities and chronic respiratory symptoms are presented in Table 2. For comorbidities, participants in groups I, II, III, and IV exhibited a significantly higher risk of developing asthma than participants in group V (unadjusted P_trend <0.001; adjusted P_trend <0.001). Furthermore, there was a significant association between FEV_0.5/FVC and chronic bronchitis and emphysema (unadjusted P_trend <0.001; adjusted P_trend <0.001). No statistically significant associations were identified between FEV_0.5/FVC and congestive heart failure, stroke, cancer, or hypertension (all adjusted P_trend >0.05).

For chronic respiratory symptoms, statistically significant associations were observed between FEV_0.5/FVC and chronic cough, chronic phlegm, wheezing, and dyspnea (all unadjusted P_trend <0.001; all adjusted P_trend <0.001).

Association between FEV_0.5/FVC and all-cause mortality risk

Overall, 6,295 all-cause deaths were recorded over the median follow-up period of 308 months. Figure 3 presents the Kaplan-Meier survival curves for the risk of all-cause mortality in the five groups. There were 1,932 deaths (41.6%) in group I, 1,240 (27.0%) in group II, 1,319 (21.4%) in group III, 1,066 (18.5%) in group IV, and 738 (17.3%) in group V. Table 3 reports the results of the univariable and multivariable Cox regression analyses of the association between FEV_0.5/FVC and all-cause mortality risk. In the univariable Cox regression analysis, all-cause mortality risk was higher in groups I, II, III, and IV than in group V (all P<0.05; P_trend <0.001). After adjusting for confounding factors, the multivariable Cox regression analysis results were the opposite of the unadjusted results, with all-cause mortality instead lower in groups I, II, III, and IV than in group V. The results of the multivariable regression analysis were identical to those of the unadjusted regression analysis [group I: unadjusted HR 3.38, 95% confidence interval (CI): 3.10–3.68, P<0.001; group II: unadjusted HR 1.90, 95% CI: 1.73–2.08, P<0.001; group III: unadjusted HR 1.40, 95% CI: 1.28–1.54, P<0.001; group IV: unadjusted HR 1.15, 95% CI: 1.04–1.26, P=0.004; unadjusted P_trend <0.001, vs. group I: adjusted HR 0.99, 95% CI: 0.91–1.09, P=0.91; group II: adjusted HR 0.81, 95% CI: 0.74–0.89, P<0.001; group III: adjusted HR 0.80, 95% CI: 0.73–0.87, P<0.001; group IV: adjusted HR 0.81, 95% CI: 0.73–0.89, P<0.001; adjusted P_trend =0.003].

Figure 3 Mortality risk stratified by forced expiratory volume in 0.5 seconds/forced vital capacity levels at baseline. Group I, FEV_0.5/FVC ≤0.55; group II, 0.55< FEV_0.5/FVC ≤0.60; group III, 0.60< FEV_0.5/FVC ≤0.65; group IV, 0.65< FEV_0.5/FVC ≤0.70; and group V (reference), FEV_0.5/FVC >0.70. BD, bronchodilator; FEV_0.5, forced expiratory volume in 0.5 seconds; FVC, forced vital capacity.

Subgroup analyses of the association between FEV_0.5/FVC and all-cause mortality

Figure 4 presents the results of the multivariable Cox regression analysis in the different subgroups. In the male subgroup, groups II, III, and IV exhibited a lower all-cause mortality risk than group V. The female subgroup exhibited a similar trend to the male subgroup. However, in the age groups of 20–40 and 41–60 years; the subgroups with BMI values of <18.5 and ≥18.5 to <25 kg/m²; and in the non-Hispanic Black population, the difference in all-cause mortality risk between the lower and higher FEV_0.5/FVC groups was not statistically significant (all P>0.05).

Figure 4 Multivariable associations between forced expiratory volume in 0.5 seconds/forced vital capacity and mortality risk. Group I, FEV_0.5/FVC ≤0.55; group II, 0.55< FEV_0.5/FVC ≤0.60; group III, 0.60< FEV_0.5/FVC ≤0.65; group IV, 0.65< FEV_0.5/FVC ≤0.70; and group V (reference), FEV0.5/FVC >0.70. Adjusted for age, sex, smoking status, body mass index, and race. BMI, body mass index; BD, bronchodilator; CI, confidence interval; FEV_0.5, forced expiratory volume in 0.5 seconds; FVC, forced vital capacity; HR, hazard ratio.

Non-linear association between FEV_0.5/FVC and all-cause mortality risk

The results of the RCS analysis demonstrated an L-shaped association between FEV_0.5/FVC and all-cause mortality before adjustment. The value of the inflection point prior to adjustment was approximately 0.72 (Figure 5A). After adjusting for confounding factors, a U-shaped association was observed between FEV_0.5/FVC and all-cause mortality. The calculation yielded an adjusted inflection point of 0.65. The HR decreased gradually prior to reaching the inflection point and increased similarly after reaching a minimum at the inflection point (Figure 5B). This indicated that before the inflection point, participants with lower FEV_0.5/FVC demonstrated an elevated risk of all-cause mortality.

Figure 5 Nonlinear associations between forced expiratory volume in 0.5 seconds/forced vital capacity and mortality risk. (A) Unadjusted model: restricted cubic spline (RCS) depicting the nonlinear associations between FEV_0.5/FVC and mortality risk without covariate adjustment. (B) Adjusted model: RCS depicting the associations after adjustment for age, sex, smoking status, body mass index, and race. BD, bronchodilator; CI, confidence interval; FEV_0.5, forced expiratory volume in 0.5 seconds; FVC, forced vital capacity; HR, hazard ratio.

Discussion

The findings of this study demonstrate that participants with a reduced FEV_0.5/FVC exhibited a significantly increased risk of four chronic respiratory symptoms, eight comorbidities, and all-cause mortality than participants with elevated FEV_0.5/FVC. Furthermore, a significant non-linear relationship was observed between FEV_0.5/FVC and all-cause mortality risk. It is of particular interest that after adjustment for age, sex, BMI, race, and smoking status, the non-linear association between FEV_0.5/FVC and all-cause mortality manifested as a U-shaped pattern. These outcomes were largely consistent across the subgroup analyses.

The present study is the first analysis of the association between FEV_0.5/FVC and respiratory health prognosis in adults. The analysis involved an in-depth exploration from multiple perspectives, including chronic respiratory symptoms and comorbidities. Subgroup analyses further enhanced the understanding of this research topic. The study utilized a large sample from the NHANES database and used advanced statistical methods to bolster the robustness of the results. The median follow-up period of 308 months provided valuable long-term data for the study. Moreover, rigorous quality control criteria were implemented during data collection to ensure the reliability of the pulmonary function data. Given the strengths and innovative nature of this study, we anticipate that it will lay a solid foundation for future research into the clinical applications of FEV_0.5/FVC for predicting health prognosis in adults.

FEV_0.5 is defined as the most rapid expiratory volume within 0.5 seconds from maximal inspiration to the residual volume. It is distinguished from FEV₁, which is defined as the most rapid expiratory volume within the first second. This distinction highlights the focus of FEV_0.5 on the initial stage of expiration, whereas FEV₁ encompasses the overall expiratory volume within the first second. Given that FEV_0.5 is focused on the early stage of expiration, we hypothesized that it may be more sensitive to early airway narrowing or obstruction. In comparison, FEV₁, given that it encompasses the subsequent expiratory phase, may not decline significantly in the early stage of disease. A reduction in FEV_0.5/FVC may therefore be indicative of the onset of airway disease at an earlier stage. In contrast, a notable decline in FEV₁/FVC is typically observed at more advanced stages of disease. In clinical practice, FEV₁/FVC is a key indicator used for the diagnosis and assessment of COPD, especially when the ratio is <70%, which usually suggests airflow limitation. In contrast, FEV_0.5/FVC, as a recently introduced metric, may prove advantageous in terms of its ability to provide supplementary insight into the early diagnosis and therapeutic monitoring of disease.

This study identified a U- or L-shaped association between FEV_0.5/FVC and all-cause mortality risk. Our findings indicated that a lower FEV_0.5/FVC was associated with an elevated all-cause mortality risk. Nevertheless, this association was only observed when FEV_0.5/FVC was <0.72. After adjustment, a U-shaped association was observed between FEV_0.5/FVC and all-cause mortality. The underlying mechanisms responsible for this U-shaped association remain unclear; however, several potential explanations exist.

It is first necessary to distinguish between obstructive and restrictive ventilatory disorders in the context of varying pulmonary function states. In obstructive pulmonary diseases such as small airway obstruction, the reduction in expiratory flow due to airway blockage results in a decrease in FEV_0.5, while FVC remains relatively normal or is only minimally reduced. This leads to a reduction in FEV_0.5/FVC (20,21). In contrast, in restrictive lung diseases such as interstitial lung disease, alveolar expansion is limited, resulting in a decrease in lung volume (both FVC and total lung capacity) with a smaller decrease in (or almost unchanged) FEV_0.5, leading to a normal or increased FEV_0.5/FVC (22). Both obstructive and restrictive airway ventilation dysfunction impact the risk of all-cause mortality to varying degrees, forming the two ends of the U-shaped curve.

Second, it is important to consider inter-individual variability. Significant heterogeneity exists in pulmonary function and airway responsiveness among individuals. This biological diversity may lead to a reduction in the risk of all-cause mortality within a specific range of FEV_0.5/FVC. Outside of this range, the risk of mortality increases. However, this phenomenon remains to be validated in further scientific research.

Currently, there is a scarcity of research focusing on the novel indicator of FEV_0.5/FVC. Nève et al. demonstrated the efficacy of FEV_0.75/FVC and FEV_0.5/FVC in assessing asthma control and wheezing disorders in preschool children (12), yet the clinical application of FEV_0.5/FVC in adults had not been investigated previously, which gives novelty to the present study.

Previous studies have demonstrated that FEV₁/FVC exhibits a certain association with the risk of various pathological conditions, including congestive heart failure (23), stroke (24), asthma (25), chronic bronchitis (26), emphysema (27), cancer, diabetes mellitus (28), hypertension, chronic cough (29), chronic phlegm (29), wheezing (29), and dyspnea. The results of the analyses of FEV_0.5/FVC demonstrated a consistent association between FEV₁/FVC and the majority of the analyzed comorbidities and chronic respiratory symptoms. However, in certain groups, the results for FEV₁/FVC and FEV_0.5/FVC were inconsistent. Baum et al. demonstrated that FEV₁/FVC is associated with an increased risk of heart failure (23). However, in contrast with their hypothesis, our findings revealed no statistically significant association between FEV_0.5/FVC and congestive heart failure after adjustment.

Another previous study demonstrated a significant association between FEV₁/FVC and the risk of COPD-related mortality (4). The majority of academic research has thus far focused on exploring the association between FEV₁/FVC and the risk of COPD-related mortality. But to date, no systematic research studies have evaluated the relationship between FEV_0.5/FVC and all-cause mortality risk. Therefore, the present study overcomes the limitations of existing research by exploring the association between FEV_0.5/FVC and all-cause mortality risk in adults for the first time.

Although this study has yielded several pivotal findings, we must acknowledge the potential limitations inherent to our research. First, because the NHANES conducted the postbronchodilator spirometry in only a subset of patients with obstructive pulmonary disease, our analysis was primarily based on the spirometry data obtained prior to bronchodilator use. The existing literature suggests that postbronchodilator spirometry may offer more precise predictions of mortality risk than prebronchodilator measurements. However, the discrepancies between the two sets of measurements are relatively minor, thus our findings are still considered valuable (30). Second, the scope of our study was confined to adult residents of the United States. Given the potential impact of racial differences, the data obtained may not be generalizable to individuals from other countries and regions. Third, despite rigorous adjustment for major covariates such as sex, age, race, BMI, and smoking status, this study may still be subject to residual confounding from unmeasured factors. Notably, environmental exposures (e.g., air pollution) and medication use (e.g., inhaled corticosteroids), which were not captured in NHANES, could potentially influence all-cause mortality risk (31-34). Finally, due to the absence of longitudinal data for the metric of FEV_0.5/FVC, we were unable to investigate the potential association between the temporal changes in FEV_0.5/FVC and respiratory health outcomes.

Conclusions

This study demonstrated a negative association between the FEV_0.5/FVC ratio and respiratory health prognosis in adults. Future research will focus on delineating the normal range of FEV_0.5/FVC in healthy individuals.

Acknowledgments

We thank all the participants who volunteered as part of the National Health and Nutrition Examination Survey.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-319/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-319/prf

Funding: This work was supported by the Foundation of Guangzhou National Laboratory (grant Nos. SRPG22-016 and SRPG22-018); the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (grant No. SKLRD-L-202402); and the Plan on Enhancing Scientific Research in Guangzhou Medical University (grant No. GMUCR2024-01012).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-319/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in strict accordance with the ethical principles stated in the Declaration of Helsinki and its subsequent amendments. The protocol for the NHANES study was formally approved by the Research Ethics Review Board of NCHS (with the respective protocol numbers #2005-06 and #2011-17).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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