Significance of FEV3/FEV6 in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD: Analysis of the SPIROMICS Cohort

doi:10.1016/j.chest.2021.10.046

Chest

Volume 161, Issue 4, April 2022, Pages 949-959

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Background

Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease.

Research Question

Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV₃/FEV₆) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?

Study Design and Methods

The study included 832 current and former smokers with post-bronchodilator FEV₁/FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV₃/FEV₆ based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV₃ and FEV₆. Regression modeling was used to evaluate the relationship between baseline FEV₃/FEV₆ and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD.

Results

FEV₃/FEV₆ less than the LLN at baseline, defined as reduced compared with FEV₃/FEV₆ at or above the LLN, was associated with lower FEV₁, poorer health status (St. George’s Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV₃ and FEV₆ showed excellent agreement between repeat measurements. A reduced FEV₃/FEV₆ was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV₃/FEV₆ was also associated with development of COPD according to spirometry results (post-bronchodilator FEV₁/FVC < 0.7) during study follow-up.

Interpretation

FEV₃/FEV₆ is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV₃/FEV₆ can identify those at risk for future development of COPD and respiratory exacerbations.

Clinical Trial Registration

ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov: ClinicalTrials.gov.

Graphical Abstract

Section snippets

Study Design and Participants

SPIROMICS is a multicenter observational study that enrolled current and former smokers (≥ 20 pack-years) aged 40 to 80 years with and without COPD defined according to post-bronchodilator spirometry results who were followed up longitudinally from 2010 to 2015.²⁰ This study focused on participants who were current or former smokers (≥ 20 pack-years) without a diagnosis of COPD at baseline (post-bronchodilator FEV₁/FVC ≥ 0.7) with available FEV₃ and FEV₆ measurements (N = 832). In this study,

Results

In the cohort of current or former smokers without COPD (≥ 20 pack-years with post-bronchodilator FEV₁/FVC ≥ 0.7), pre-bronchodilator FEV₃/FEV₆ was abnormal in 17.2% (n = 143) of participants at baseline. The corresponding proportions for the overall SPIROMICS cohort with available FEV₃/FEV₆ data are included in e-Table 2. Median follow-up time was 48.0 months for participants with normal FEV₃/FEV₆ and 50.4 months for participants with reduced FEV₃/FEV₆. Baseline characteristics of this cohort

Discussion

The current study evaluated FEV₃/FEV₆ as a metric of early airflow obstruction and explored the role and significance of this spirometric measure in predicting outcomes in the SPIROMICS cohort. Among current and former smokers without COPD (baseline post-bronchodilator FEV₁/FVC ≥ 0.7), we found that participants with a reduced pre-bronchodilator FEV₃/FEV₆ had a greater burden of respiratory disease, more emphysema, and functional SAD by quantitative imaging, and higher rates of respiratory

Interpretation

A reduced FEV₃/FEV₆ in current and former smokers without COPD identifies individuals who are at risk of experiencing respiratory exacerbations and developing COPD. It is a simple, routinely available, and reproducible metric with potential to aid with early identification and timely intervention in people at risk for COPD. The study data suggest that interpretation of spirometry results beyond FEV₁ and FVC can offer additional relevant clinical insights in this population.

Take-home Points

Study

Acknowledgments

Author contributions: D. M., I. Z. B., and N. Y. had full access to the data and take responsibility for the integrity of the data and accuracy of the analysis; N. Y., D. M., R. G. Buhr, D. P. T., and I. Z. B. were involved in the design of the analysis; N. Y., D. M., R. G. Buhr, D. P. T., and I. Z. B. contributed to the drafting of the manuscript; and C. B. C., D. C., , E. A. H., F. J. M., J. L. C., J. M. W., M. A., M. B. D., M. K. H., R. G. Barr, R. P., S. F., V. K., V. E. O., W. H. A. , P.

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Potential pre-COPD indicators in association with COPD development and COPD prediction models in Chinese: a prospective cohort study
2024, The Lancet Regional Health - Western Pacific
Lung injury might take place before chronic obstructive pulmonary disease (COPD) occurs. A clearer definition of “pre-COPD” based on the effects of potential indicators on increasing risk of COPD development and a prediction model involving them are lacking.
A total of 3526 Chinese residents without COPD aged 40 years or older derived from the national cross-sectional survey of COPD surveillance in 2014–2015 were followed up for a mean of 3.59 years. We examined the associations of chronic bronchitis, preserved ratio impaired spirometry (PRISm), low peak expiratory flow (PEF), spirometric small airway dysfunction (sSAD), low maximal mid-expiratory flow (MMEF), low forced expiratory flow 50% of pulmonary volume (FEF50), and low FEF75 with subsequent COPD and constructed a prediction model with LASSO-Cox regression.
235 subjects in the cohort developed COPD during the follow-up. Subjects with PRISm, low PEF, sSAD, low MMEF, low FEF50, and low FEF75 had an increased risk of developing COPD (adjusted hazard ratio [HR] ranging from 1.57 to 3.01). Only chronic bronchitis (HR 2.84 [95% CI 1.38–5.84] and 2.94 [1.43–6.04]) and sSAD/low MMEF (HR 2.74 [2.07–3.61] and 2.38 [1.65–3.43]) showed effects independent of the other indicators and their concurrence had the strongest effect (HR 5.89 and 4.80). The prediction model including age, sex, low MMEF, low FEF50, and indoor exposure to biomass had good performance both internally and temporally. The corrected C-index was 0.77 (0.72–0.81) for discrimination in internal validation. For temporal validation, the area under the receiver operating characteristic curve was 0.73 (0.63–0.83). Good calibration was indicated in plot for internal validation and by Hosmer–Lemeshow test for temporal validation.
Individuals with concurrent chronic bronchitis and sSAD/low MMEF indicating pre-COPD optimally require more high attention from physicians. Our prediction model could serve as a multi-dimension tool to predict COPD comprehensively.
The Ministry of Finance and the Ministry of Science and Technology of the People's Republic of China and the National Natural Science Foundation of China.
在慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)出现前, 肺损伤可能已经发生。目前尚缺乏依据潜在指标对升高COPD发生风险的影响而产生的更明确的"慢阻肺前期"的定义, 以及包含这些潜在指标的慢阻肺发病预测模型。
本研究基于2014–2015年中国居民慢阻肺监测横断面调查, 对3526名40岁及以上的非慢阻肺居民进行了平均3.59年的随访；旨在分析慢性支气管炎、保留比值的肺功能损伤 (preserved ratio impaired spirometry, PRISm)、低呼气峰流速 (peak expiratory flow, PEF)、小气道功能障碍 (spirometric small airway dysfunction, sSAD)、低最大呼气中期流速 (maximal mid-expiratory flow, MMEF)、低呼出50%用力肺活量时的最大呼气流速 (forced expiratory flow 50% of pulmonary volume, FEF50)、低FEF75与COPD发生的关系, 并采用LASSO-Cox回归构建预测模型。
本前瞻性队列中共有235名研究对象在随访期间发展为COPD患者。PRISm、低PEF、sSAD、低MMEF、低FEF50和低FEF75者发生COPD的风险增加(调整后的风险比 [hazard ratio, HR] 在1.57至3.01之间)。只有慢性支气管炎 (HR 2.84 [95% CI 1.38–5.84] 和2.94 [1.43–6.04]) 和sSAD/低MMEF (HR 2.74 [2.07–3.61] 和2.38 [1.65–3.43]) 的效应独立于其他指标, 且慢性支气管炎和sSAD共存或慢性支气管炎和低MMEF共存的效应最强 (HR 5.89和4.80)。本研究构建的预测模型因子包括年龄、性别、低MMEF、低FEF50和室内生物燃料暴露。该模型在内部验证和外部验证中均表现出良好的预测性能。内部验证中该模型的区分度即校正后C-index为0.77 (0.72–0.81)。外部验证中受试者工作特征曲线下面积为0.73 (0.63–0.83)。该模型在内部验证的校准图和外部验证的Hosmer-Lemeshow检验中均显示出良好的校准度。
慢性支气管炎和sSAD/低MMEF是提示COPD前期的最佳指标, 同时存在这两种表现的个体需引起临床医生的高度重视。本研究构建的预测模型可以作为一个多维度的综合预测COPD的工具。
中华人民共和国财政部、科学技术部和国家自然科学基金。
Small airways obstruction and its risk factors in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study
2023, The Lancet Global Health
Citation Excerpt :
A potential explanation is that damage to the small airways occurs early in the disease process. Therefore, the higher prevalence of small airways obstruction in this study than for traditional airflow obstruction reflects the inclusion of individuals with early airflow obstruction who might progress to chronic airflow obstruction in later life.8,12 Only studies in smokers and hospital-based populations have suggested a link between small airways obstruction and subsequent chronic obstructive pulmonary disease,8,12 and further studies, preferably longitudinal, in general populations are needed.
Small airways obstruction is a common feature of obstructive lung diseases. Research is scarce on small airways obstruction, its global prevalence, and risk factors. We aimed to estimate the prevalence of small airways obstruction, examine the associated risk factors, and compare the findings for two different spirometry parameters.
The Burden of Obstructive Lung Disease study is a multinational cross-sectional study of 41 municipalities in 34 countries across all WHO regions. Adults aged 40 years or older who were not living in an institution were eligible to participate. To ensure a representative sample, participants were selected from a random sample of the population according to a predefined site-specific sampling strategy. We included participants' data in this study if they completed the core study questionnaire and had acceptable spirometry according to predefined quality criteria. We excluded participants with a contraindication for lung function testing. We defined small airways obstruction as either mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF_25–75) less than the lower limit of normal or forced expiratory volume in 3 s to forced vital capacity ratio (FEV₃/FVC ratio) less than the lower limit of normal. We estimated the prevalence of pre-bronchodilator (ie, before administration of 200 μg salbutamol) and post-bronchodilator (ie, after administration of 200 μg salbutamol) small airways obstruction for each site. To identify risk factors for small airways obstruction, we performed multivariable regression analyses within each site and pooled estimates using random-effects meta-analysis.
36 618 participants were recruited between Jan 2, 2003, and Dec 26, 2016. Data were collected from participants at recruitment. Of the recruited participants, 28 604 participants had acceptable spirometry and completed the core study questionnaire. Data were available for 26 443 participants for FEV₃/FVC ratio and 25 961 participants for FEF_25–75. Of the 26 443 participants included, 12 490 were men and 13 953 were women. Prevalence of pre-bronchodilator small airways obstruction ranged from 5% (34 of 624 participants) in Tartu, Estonia, to 34% (189 of 555 participants) in Mysore, India, for FEF_25–75, and for FEV₃/FVC ratio it ranged from 5% (31 of 684) in Riyadh, Saudi Arabia, to 31% (287 of 924) in Salzburg, Austria. Prevalence of post-bronchodilator small airways obstruction was universally lower. Risk factors significantly associated with FEV₃/FVC ratio less than the lower limit of normal included increasing age, low BMI, active and passive smoking, low level of education, working in a dusty job for more than 10 years, previous tuberculosis, and family history of chronic obstructive pulmonary disease. Results were similar for FEF_25–75, except for increasing age, which was associated with reduced odds of small airways obstruction.
Despite the wide geographical variation, small airways obstruction is common and more prevalent than chronic airflow obstruction worldwide. Small airways obstruction shows the same risk factors as chronic airflow obstruction. However, further research is required to investigate whether small airways obstruction is also associated with respiratory symptoms and lung function decline.
National Heart and Lung Institute and Wellcome Trust.
For the Dutch, Estonian, French, Icelandic, Malay, Marathi, Norwegian, Portuguese, Swedish and Urdu translations of the abstract see Supplementary Materials section.
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: The positions in the article do not necessarily reflect those of the Department of Veterans Affairs.

: FUNDING/SUPPORT: The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) was supported by contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute [HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C] and grants from the NIH/National Heart, Lung, and Blood Institute [U01 HL137880 and U24 HL141762]. It was supplemented by contributions made through The Foundation for the National Institutes of Health and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; and Viatris.

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Chest

COPD: Original ResearchSignificance of FEV3/FEV6 in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD: Analysis of the SPIROMICS Cohort

Background

Research Question

Study Design and Methods

Results

Interpretation

Clinical Trial Registration

Graphical Abstract

Section snippets

Study Design and Participants

Results

Discussion

Interpretation

Take-home Points

Acknowledgments

Chest

Chest

Chest

Respir Med

Acad Radiol

Respir Med

Chest

The role of small airways in obstructive airway diseases

Eur Respir Rev

The pathology of small airways disease in COPD: historical aspects and future directions

Respir Res

Techniques of assessing small airways dysfunction

Eur Clin Respir J

Small airway disease in chronic obstructive pulmonary disease: insights and implications for the clinician

Curr Opin Pulm Med

Interpretative strategies for lung function tests

Eur Respir J

Clinical and radiologic disease in smokers with normal spirometry

JAMA Intern Med

Clinical and radiographic predictors of GOLD-unclassified smokers in the COPDGene study

Am J Respir Crit Care Med

Clinical significance of symptoms in smokers with preserved pulmonary function

N Engl J Med

At the root: defining and halting progression of early chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity

Eur Respir J

Respiratory symptoms in smokers with normal spirometry: clinical significance and management considerations

Curr Opin Pulm Med

Re-defining lower limit of normal for FEV1/FEV6, FEV1/FVC, FEV3/FEV6 and FEV3/FVC to improve detection of airway obstruction

Chronic Obstr Pulm Dis

FEV(6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction

Am J Respir Crit Care Med

Should forced expiratory volume in six seconds replace forced vital capacity to detect airway obstruction?

Eur Respir J

Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)

Thorax

Standardisation of spirometry

Eur Respir J

COPD: Original Research
Significance of FEV₃/FEV₆ in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD: Analysis of the SPIROMICS Cohort