Abstract
Supernormal lung function is associated with fewer cardiovascular and respiratory events and a survival benefit independent from major risk factors https://bit.ly/371l3ut
To the Editor:
Cardiovascular and respiratory diseases are major contributors to global deaths [1]. Although low lung function is a risk factor for early death, like hypertension and hypercholesterolaemia [2], evaluation of lung function in primary care is not prioritised as highly as blood pressure or cholesterol measurements [3]. Also, public health authorities have remained silent on major health challenges other than smoking relevant for development and preservation of normal lung function from birth to old age. It is now increasingly evident that low lung function in childhood may affect general health throughout life [4–8]. It therefore seems likely that improvement of lung function on a population-scale may be associated with lower morbidity and mortality. We therefore tested the hypothesis that supernormal lung function is associated with lower morbidity and mortality.
We included 108 246 individuals aged 20–100 years from the Copenhagen General Population Study, an ongoing Danish contemporary population-based cohort recruited between 2003 and 2015 [9–11]. All participants completed questionnaire, underwent physical examination, and provided blood for biochemical analyses. Pre-bronchodilator forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured [12]. The upper and lower limit of normal (ULN and LLN) for FVC and FEV1 were defined as the highest or lowest 5th percentile of the predicted value, calculated as the mean value ±1.645 standard deviations according to internally derived reference equations [10, 12]. Normal lung function was defined as FVC≥LLN and ≤ULN, and supernormal lung function as FVC>ULN. Individuals with below normal lung function, i.e. FEV1<LLN and/or FVC<LLN, were excluded.
Information on acute admissions and vital status was obtained from the national Danish Patient Registry and Danish Civil Registration System, respectively, recorded until December 2018. Information on cause of death was obtained from the national Danish Causes of Death Registry recorded until December 2016. Admission and death due to respiratory disease (International Classification of Diseases (ICD)-10: J00–J99) and cardiovascular disease (ICD-10 :E00–E99) was based on the underlying cause. Any acute admission also included other diseases besides respiratory and cardiovascular. Death due to cancer (ICD-10: C00–C99) was included as a negative control outcome.
Cox regression was used to determine risk of admission and death during follow-up. Age was used as the underlying timescale, and hence automatically adjusted for in the analyses, while accounting for delayed time-entry (i.e. left truncation meaning individuals are at risk only from study entry). Analyses were adjusted for well-known major respiratory and cardiovascular risk factors obtained at baseline examination, that is, age (as timescale), sex, measured body mass index (BMI, kg·m−2), measured waist-hip ratio, smoking status (never, former, or current), cumulative tobacco consumption (pack-years), socioeconomic status based on education after school (no education, high school, other education up to 3 years, vocational training, longer education at least 3 years, and university education) and annual household income (converted as 1 Danish krone to 0.13 EUR: <26 000 EUR, 26 000–52 000 EUR, 52 000–78 000 EUR, 78 000–104 000 EUR, and >104 000 EUR), leisure time physical activity (none or light activity <2 h per week, light activity 2–4 h per week, light activity >4 h per week or heavy activity 2–4 h per week, and heavy activity >4 h per week or regular exercises per week), blood pressure, cholesterol, alcohol consumption and diabetes. Analyses were performed using STATA/SE 13.1 for Windows (StataCorp, College Station, TX, USA), and a two-sided p-value <0.05 was considered significant.
Among 108 246 individuals from the general population, 88 478 (82%) had normal lung function, 5948 (5%) had supernormal lung function, and 13 820 (13%) had below normal lung function. Individuals with supernormal lung function had mean FVC of 5.21 L (corresponding to FVC 130% of predicted), whereas individuals with normal lung function had mean FVC of 3.95 L (FVC 101% of predicted). Compared to individuals with normal lung function, those with supernormal lung function were slightly younger, taller, had lower cumulative tobacco consumption, and less active smoking (figure 1a). Although highly statistically significant due to the large sample-size, no clinically relevant differences could be observed for well-known major respiratory and cardiovascular risk factors, including BMI, low physical activity, blood pressure, cholesterol, alcohol consumption and diabetes.
During up to 15 years follow-up (median 9.2 years, interquartile range 5.2), we observed 63 225 acute admissions (7452 respiratory; 15 044 cardiovascular) and 8234 deaths (341 respiratory; 1408 cardiovascular). Compared to individuals with normal lung function, multivariable adjusted hazard ratios for individuals with supernormal lung function were 0.93 (95% CI 0.90–0.97) for any acute admission, 0.80 (95% CI 0.71–0.90) for respiratory admission, and 0.91 (95% CI 0.85–0.99) for cardiovascular admission (figure 1b). Corresponding hazard ratios were 0.84 (95% CI 0.76–0.93) for all-cause mortality, 0.49 (95% CI 0.25–0.98) for respiratory mortality, and 0.57 (95% CI 0.42–0.79) for cardiovascular mortality. Median survival was 2.3 years longer in those with supernormal versus normal lung function. The two groups did not differ in cancer mortality with corresponding hazard ratio of 0.91 (95% CI 0.75–1.11).
Results were similar in sensitivity analyses. When supernormal lung function was defined by calculating the predicted values according to Global Lung Function Initiative reference equations [13], multivariable adjusted corresponding hazard ratios were 0.85 (95% CI 0.76–0.96) for all-cause mortality, 0.33 (95% CI 0.12–0.89) for respiratory mortality, and 0.56 (95% CI 0.39–0.82) for cardiovascular mortality. Corresponding hazard ratios were 0.82 (95% CI 0.73–0.93), 0.44 (95% CI 0.19–0.99) and 0.66 (95% CI 0.47–0.93) when supernormal lung function was defined with FEV1 instead of FVC, and were 0.85 (95% CI 0.76–0.94), 0.40 (95% CI 0.19–0.86) and 0.55 (95% CI 0.40–0.77) when supernormal lung function was defined as FVC in the upper 5th age, sex and height adjusted percentile without use of reference equations. Corresponding hazard ratios were 0.86 (95% CI 0.72–1.04), 0.13 (95% CI 0.10–3.67) and 0.71 (95% CI 0.43–1.18) in never-smokers, and were 0.81 (95% CI 0.71–0.93), 0.59 (95% CI 0.29–1.21) and 0.49 (95% CI 0.33–0.73) in ever-smokers, with no evidence of interaction.
In a Danish contemporary population-based cohort with 108 246 randomly selected adults followed for up to 15 years, we found that supernormal lung function is associated with fewer cardiovascular and respiratory events and a survival benefit independent from major risk factors. To our knowledge, this is the first study investigating supernormal lung function in the general population.
Individuals with supernormal lung function did not differ clinically from individuals with normal lung function with regard to age, sex, height, and major respiratory and cardiovascular risk factors, suggesting that other factors, possibly related to lung development, may explain the difference in lung function. In support of the lung development hypothesis, it has been suggested that individuals with supernormal lung function are those with a high peak in early adulthood [4]. Also, it has been shown that children with persistently high or low lung function seem to follow the same lung function trajectory up until early and late adulthood, and early life factors were the most important determinants of these lung function trajectories [14, 15].
Strengths of the present study include a large contemporary general population cohort with randomly selected individuals, and information on clinically relevant morbidity and mortality outcomes without any losses to follow-up.
A potential limitation of the present study is that body plethysmography was not used to determine lung capacity, as it is not feasible to apply this highly specialised method in large-scale population-based cohorts, whereas spirometers are readily accessible and used in clinical practice. We did also observe similar results when supernormal lung function was defined with FEV1 instead of FVC, which suggests that supernormal lung function could in principle have been defined with other lung function measures.
The benefit of having a supernormal lung function will likely be less prioritised than the detrimental effects of a low lung function. Nonetheless, the present study could be viewed as a first step in exploring the relevance of development and preservation of best possible lung function from birth to old age for public health. Our results suggest that supernormal lung function is associated with fewer cardiovascular and respiratory events and a survival benefit independent from major risk factors.
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Footnotes
Author contributions: Y. Çolak and S. Afzal had full access to all the data in the study and had final responsibility for the decision to submit for publication. Y. Çolak, B.G. Nordestgaard, J. Vestbo, P. Lange and S. Afzal contributed to the study concept and design. Y. Çolak, B.G. Nordestgaard, J. Vestbo, P. Lange and S. Afzal collected, analysed, or interpreted the data. Y. Çolak wrote the draft manuscript and performed the statistical analyses. Y. Çolak, B.G. Nordestgaard, J. Vestbo, P. Lange and S. Afzal revised the manuscript for important intellectual content. B.G. Nordestgaard obtained funding. B.G. Nordestgaard provided administrative, technical, or material support. S. Afzal supervised the study.
Conflict of interest: B.G. Nordestgaard has nothing to disclose.
Conflict of interest: J. Vestbo reports personal fees for consultancy from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis, Almirall, AstraZeneca and Bioxydyn, personal fees for lectures from GlaxoSmithKline, Chiesi Pharmaceuticals, Novartis, AstraZeneca and Boehringer Ingelheim, outside the submitted work; and the author's spouse is a former employee of GlaxoSmithKline, AstraZeneca and Ferring.
Conflict of interest: P. Lange reports grants and personal fees from Almirall, Boehringer Ingelheim and GSK, personal fees from AstraZeneca, Novartis, Nycomed, Pfizer and Mundipharma, outside the submitted work.
Conflict of interest: S. Afzal has nothing to disclose.
Conflict of interest: Y. Çolak reports personal fees from Boehringer Ingelheim, AstraZeneca and Sanofi Genzyme outside the submitted work.
Support statement: This study was funded by the Lundbeck Foundation. The funder had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Y. Çolak and S. Afzal had full access to all data in the study and had final responsibility for the decision to submit for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 3, 2020.
- Accepted November 13, 2020.
- Copyright ©ERS 2021