FEV₁: More Than a Measurement of Lung Function, A Biomarker of Health

Clinicians have long used spirometry measurements, including FEV₁ and FVC, to help with the diagnosis, monitoring, and prognostication of lung diseases. More recently, various lung function trajectories over the life course have been identified (1). The inability to reach normal peak FEV₁ in early adulthood has been recognized as a risk factor for chronic obstructive pulmonary disease later in life (2). In addition, a low FEV₁ in early adulthood has been associated with a higher risk of early pulmonary and nonpulmonary comorbidities and premature all-cause mortality (3). However, how the variation of FEV₁ within the normal range affects long-term clinical outcomes has been little investigated.

In this issue of the Journal, Cannon and colleagues (pp. 1229–1237) aimed to understand the association between FEV₁ in the normal range (defined as ⩾80% predicted using race-neutral Global Lung Function Initiative reference equations) and all-cause 20-year mortality in two cohorts, the Fire Department of the City of New York (FDNY; mean age, 38.7 yr) and the third National Health and Nutrition Examination Survey (NHANES; mean age, 37.7 yr) (4). Compared with participants with FEV₁ ⩾ 120% predicted, those in progressively lower lung function categories had an increasingly higher risk of death in both cohorts after adjustment for age, sex, race/ethnicity, smoking history, and work assignment (in FDNY only). Notably, those with FEV₁ 80–89% predicted were about twice as likely to die in the subsequent 20 years, with hazard ratios (HRs) of 1.90 (95% confidence interval [CI], 1.36–2.65) and 2.40 (95% CI, 1.51–3.80) in FDNY and NHANES, respectively. When analyzed as a continuous variable, each 10% increment in FEV₁% predicted within the normal range was associated with lower mortality in FDNY (HR, 0.85; 95% CI, 0.80–0.91) and NHANES (HR, 0.77; 95% CI, 0.71–0.84). In both cohorts, the HR for mortality continuously decreased between FEV₁ 80% and 110% predicted, with attenuation of effect for FEV₁ > 110% predicted. As expected, FEV₁ and FVC were highly correlated in both cohorts. Sensitivity analyses with absolute FEV₁ in liters, FEV₁% predicted using Hankinson reference equations, and the addition of participants with FEV₁ < 80% predicted all yielded similar results. Of note, respiratory-related deaths accounted for <5% of all deaths in both cohorts.

This study, which sheds much-needed light on an important clinical question, has several strengths. It included two large independent cohorts, one occupational (FDNY) and the other more representative of the general U.S. population (NHANES), which supports the generalizability of its findings. Furthermore, the various sensitivity analyses confirm the consistency of results across different FEV₁ modeling methods. Vital status and date of death were accurately determined using the National Death Index over a long period of follow-up. One limitation of this analysis is that it did not account for several potential confounders, including lifestyle habits (e.g., diet, exercise, more detailed smoking history), comorbidities (e.g., cardiovascular, asthma, obesity), early-life events (e.g., preterm birth, low birth weight, childhood asthma, childhood lower respiratory tract infections), and environmental exposures (e.g., air pollution, secondhand smoke). Nonetheless, this analysis still highlights the prognostic implication of lower lung function within the normal range, even when measured at one point in time in younger individuals.

In clinical practice, an FEV₁ 80–100% predicted is often overlooked as just “normal,” but the more important question is whether it is as high as it can be for a given person. Some individuals may not be able to exceed their normal but below-average FEV₁ because of genetic determinants, remote events that affected their lung growth, or more recent events that irreversibly injured parts of their lungs. However, others may be living with a lung function that is significantly below their potential even though it is technically within normal limits. Identifying these individuals is important, because recognizing and addressing their modifiable risk factors may help them reach their peak lung function and, by extension, likely experience better long-term clinical outcomes. Higher omega-3 fatty acid intake, higher physical activity, loss of excess weight, early diagnosis and treatment of asthma, smoking cessation, and decreased exposure to air pollution have all been linked to improved lung function (5–10).

To identify individuals with a lung function below their achievable peak, knowledge of their baseline lung function would be helpful. However, unfortunately, spirometry is hardly ever obtained as part of routine health checks in early adulthood. Contrast this with several vital signs and blood biomarkers that are not only routinely measured but also clinically interpreted in a personalized context. A reportedly normal temperature of 37.5°C or blood pressure of 120/80 mm Hg may raise concern in patients who “live low” for their baseline temperature and blood pressure. A creatinine of 1.0 mg/dl, although in the normal range, would be diagnostic of acute kidney injury in someone whose baseline creatinine is 0.5 mg/dl. Yet, an FEV₁ of 82% predicted would more often than not just be dismissed as normal in the setting of a likely absence of an established baseline.

Repeated calls to integrate spirometry in routine health checks have unfortunately largely failed during the past 50 years (11, 12). We still need to purposely solidify the role of spirometry as a powerful biomarker of health. To this end, we should demonstrate the prognostic value of spirometry independently of and incrementally to other traditional markers of health (like blood pressure) in large representative community-based cohorts. We should also further study and highlight the actionable aspects of a low FEV₁ or FVC, including when they are in the normal but below-average range. Finally, we should investigate and understand the mechanistic links between higher spirometry measurements and better long-term survival. In the meantime, the epidemiologic association between higher lung function and better systemic health is undeniable and has stood the test of time. John Hutchinson’s original work on lung function in 1846 holds more true than ever, when he coined the term “vital capacity”—that is, the capacity for life (13).