Data from this large British cohort showed that poor lung function, characterized by low FEV1/height2, was associated with higher risk of all-cause mortality in late midlife. Similar results were found for FVC/height2 and FEV1% pred. Socioeconomic position, health behaviors, body mass index, cardiovascular risk factors, cardiovascular diseases, and inflammatory markers were used to explain this association. Our results showed inflammatory markers, and to a lesser extent behavior-related factors and chronic diseases, to explain the greater part of the association between lung function and mortality. Taken together, these factors explained one-third (FEV1/height2) to one-half (FVC/height2 and FEV1% pred) of the associations.
It is well established that lung function predicts mortality (2
), even though the mechanisms underlying this association remain unclear (5
). Researchers have examined changes in this association after adjusting for the effects of smoking, cardiovascular risk factors, or diseases (4
), but to our knowledge no study has attempted to quantify the impact of a wide range of different explanatory factors on the association. Lung function was once thought to reflect only smoking status, which was hypothesized to explain its association with mortality. However, several studies, including our study, have shown lung function to also be related to mortality in never smokers (3
). Clearly, smoking is not the only explanation for this association. Physical activity (24
) and a healthier diet (27
) have also been found to be associated with better lung function and obesity with reduced lung function (30
). Our results showed health behaviors and body mass index to explain approximately 10% of the association between lung function and mortality, with the effect being driven mainly by smoking and physical activity.
Other plausible explanatory factors include chronic comorbidity. This hypothesis is supported by the fact that patients with chronic obstructive pulmonary disease die mainly from causes other than respiratory disease (31
), arguing for the “common cause” hypothesis. Aging is accompanied by an increase in multiple chronic diseases, resulting in high comorbidity at older ages, including chronic obstructive pulmonary disease (10
). Thus, lung function might simply be a proxy for general health, explaining its association with mortality (5
). Another possibility is that impaired lung function allows excessive quantities of inhaled deleterious environmental agents to enter the body, which then leads to disease and death (33
). In the present study, chronic diseases such as coronary heart disease, stroke, and diabetes explained 12% of the association between FEV1
and mortality. However, our data did not allow us to distinguish between the 2 proposed pathways—1) lung function as a proxy for general health and 2) chronic diseases as mediating the association between lung function and mortality.
More recently, the inflammatory hypothesis has been proposed as a potential explanatory factor for the relation between lung function and other comorbid conditions leading to death (9
). Indeed, higher levels of inflammatory markers have been found among persons with impaired lung function (34
). However, it is still debated whether it is inflammation that leads to lung function deterioration or the inverse (10
). Inflammation is associated with several chronic conditions (10
) that are risk factors for mortality, such as osteoporosis, diabetes, and atherosclerosis. Thus, there are some arguments in favor of a possible role of inflammatory markers in the association between lung function and mortality, and our results support this hypothesis. Nevertheless, the importance of inflammatory markers in this association may also be due to residual confounding by smoking, since higher levels of inflammation are found in smokers. Furthermore, it has been suggested that inflammation leads to muscle wasting (10
), which is itself linked to lower lung functioning (36
). Our analysis based on never smokers and excluding persons in the lowest tertile of the fat-free-mass distribution showed inflammation to continue to play a role in mediating the association between lung function and mortality.
Strengths and weaknesses
The primary strength of this study was the large number of factors investigated to explain the association between lung function and mortality. Indeed, data on health behaviors and cardiovascular risk factors were available over a 15-year period preceding the assessment of lung function. Moreover, to our knowledge, this was the first study to assess the role of inflammatory markers. A further strength of the study was the use of adjusted survival curves that allowed us to summarize the data by avoiding potential weaknesses of the multiplicative model (40
Three limitations of this study must also be noted. First, although the sample covered a wide socioeconomic status range, with annual full-time salaries ranging from £4,995 (~$7,900) to £150,000 (~$237,400), data were obtained from white-collar civil servants and cannot be assumed to be representative of the general population. Second, the inflammatory markers considered in our study are general markers of inflammation, included in the Whitehall II Study to assess outcomes such as cardiovascular disease, and do not constitute ideal “lung function” markers. Third, our results must be interpreted with caution, since the study design did not allow us to rule out the possibility of reverse causation between lung function and other covariates. Finally, these results were based on the healthier Whitehall II participants—that is, those who were still alive and took part in the phase 7 screening and who reported no contraindicative conditions against participation in the lung function tests. Nevertheless, lower lung function still predicted mortality in this selected population, and our results are likely to have underestimated the true association.
To our knowledge, this study was the first to investigate several potential explanations underlying the well-established association between lung function and mortality. The main finding emphasizes the importance of inflammatory markers for this association. The other important explanatory factors were health behaviors and chronic diseases, such as coronary heart disease, stroke, and diabetes. These results show that multiple processes are likely to link lung function and mortality.