We have identified an association between spirometric lung volumes, and systemic inflammation, measured by serum C‐reactive protein, in young adults aged 26 and 32 years. This association was of similar magnitude in women and men and was independent of smoking, asthma and body mass index.
To our knowledge, this is the first report of an inverse association between lung function and CRP in young adults. There are numerous reports of increased markers of systemic inflammation in older adults with stable chronic obstructive pulmonary disease.8,10,11
These markers appear to reflect disease severity and functional status,10,11,12
This has usually been interpreted as being the result of the inflammatory nature of the airway disease.22,23
Since systemic inflammation is a risk factor for atherosclerosis, it has been suggested that this is one reason why patients with chronic obstructive pulmonary disease have an increased risk of cardiovascular disease.6,23
However, we have found that the association of a higher serum CRP with lower lung function is present as early as age 26
years. By this age it is very unlikely that members of this cohort will have developed either clinically significant atherosclerosis or chronic obstructive pulmonary disease. A recent report identified an inverse association between plasma fibrinogen and lung function in apparently healthy young American adults (average age 30).24
Taken together, these findings indicate that there is an association between lung function and systemic inflammation, which predates the clinical development of either disease. Moreover, the associations are equally strong in those who have never smoked and do not have asthma. Although these are prominent risk factors for the development of chronic lung disease it is clear that they do not explain the association between lung function and systemic inflammation in these young adults. The finding that association between lower lung function and CRP was independent of body mass index is important because obesity is an established risk factor for systemic inflammation in young people, a finding that has been confirmed in an earlier report from this cohort,25
and body size measurements may also influence lung function.26
These findings may help to explain epidemiological observations that have been made in older populations and are consistent with the hypothesis that systemic inflammation mediates the association between reduced lung function and cardiovascular disease. Firstly, the association between FEV1
and systemic inflammation was present in those who had never smoked and did not have asthma or other health problems. This is consistent with several observations that reduced lung function predicts cardiovascular mortality independently of smoking2
and is also consistent with the inverse association between CRP and lung function recently reported among apparently healthy older adults (mean age 50) attending for health screening14
and in general population surveys (mean ages 37 and 44).27,28
Secondly, the fall in FEV1
between age 26 and 32 was a significant predictor of blood CRP at age 32 years. This may help to explain the association between rapid FEV1
decline and cardiovascular mortality.29
Establishing whether systemic inflammation leads to reduced lung function or whether lower lung function leads to inflammation is difficult. In the longitudinal analyses CRP at age 26 did not predict the decline in FEV1
over the following six years. By contrast, the decline in FEV1
between ages 26 and 32 was a strong and significant predictor of CRP at age 32. Two other longitudinal studies in older adults also found that baseline CRP levels did not predict changes in lung function over the following 8–9 years but both found associations between decline in FEV1
and rising CRP levels.27,28
This suggests that systemic inflammation may be a consequence of a decline in lung function rather than the cause of the decline. However, CRP is an acute phase protein with a short half life30
and a much less stable measure than FEV1
. Moreover, the CRP measurements at age 26 used a low sensitivity assay. Therefore the measurement taken at age 26 may not accurately reflect the level of inflammation over the following six years. In the CARDIA study, plasma fibrinogen measured at mean age 30 appeared to predict the decline in spirometric lung volumes over the subsequent five years.24
This study did not have repeat measurements of fibrinogen after five years in order to test whether decline in lung function predicted systemic inflammation.
The association of lower spirometric lung volumes and systemic inflammation could have several explanations. It is possible that systemic inflammation damages pulmonary tissue and hence leads to deteriorating lung function. However, we found that the association was equally strong in apparently healthy study members (excluding ever smokers and those with asthma, arthritis, heart disease, cancer, diabetes, and recent major surgery or urinary tract infections). Although we will have missed some undiagnosed problems and conditions affecting other systems, this suggests that the association is unlikely to be mediated by a systemic inflammatory response to another disease process. An alternative explanation is that inflammation within the lungs may be the cause of the systemic inflammatory response, although it is clear from our findings that this inflammation is not caused by either asthma or smoking. The lungs may also have an anti‐inflammatory role, particularly as a primary defence organ against environmental toxins and it is possible that this is why people with lower lung function have increased systemic inflammation. Finally, it is possible that other factors cause both a reduction in lung function and systemic inflammation. For example, a reduced dietary intake of anti‐oxidants and vitamins has been linked to both lower lung function31,32,33
and higher levels of CRP.34,35,36
Alternatively CRP levels and lung function are likely to be influenced by genes and it is possible that these genetic influences overlap.
We analysed the data using the absolute value of FEV1
adjusting for height in the analyses rather than use FEV1
as a percentage of predicted. This is in accordance with the recommendations of Vollmer et al
Repeat analyses using the FEV1
as percentage predicted produced the same pattern of results as did analyses using FVC and the post‐bronchodilator FEV1
. The association between the FEV1
/FVC ratio and CRP was weaker and only significant in women (see Thorax
table 2). Similarly, plasma fibrinogen has been found to be associated with lower FEV1
and FVC measurements but not with reduced FEV1
This suggests that the association between lung function and systemic inflammation is more closely related to spirometric lung volumes rather than airflow obstruction.
A limitation of this study is that the measurement of CRP at age 26 years used a low sensitivity assay. It is now believed that low grade inflammation, which may impact on cardiovascular risk, may be associated with CRP levels that are not accurately detected by standard CRP assays.7
The low sensitivity assay at age 26 may have reduced our chance of detecting a prospective association between the initial CRP value and the subsequent decline in FEV1
. The differences in the assay methods may also explain the apparent fall in mean CRP levels between age 26 and 32 years. Nevertheless, CRP measurements taken at age 32 years using a high sensitivity assay provided similar cross sectional associations between CRP and FEV1
to those found at age 26 using a low sensitivity assay.
This investigation has a number of strengths. We have found similar results at two ages in a general population based cohort with a high rate of participation. The cohort members have similar health status to nationally representative samples of young adult New Zealanders38
and the distribution of CRP values is similar to that described for similar age participants in other studies.39
We have prospectively collected information on smoking and asthma and have directly measured height and weight. Lung function was measured using the same equipment for all study members and the blood samples were assayed in the same laboratory at each age.
In summary, there is a significant inverse relation between spirometric lung volumes and systemic inflammation in young adults. This association is independent of smoking and asthma history and is also independent of body mass index. While the underlying reason for this association is uncertain, the findings suggest a plausible mechanism by which a reduced FEV1 is associated with an increased risk of cardiovascular disease in a manner that is independent of smoking and known respiratory disease.