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Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible chronic airflow obstruction and by an accelerated decline in lung function. Elevated circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both markers of systemic inflammation, have been found in COPD. Their possible associations with chronic airflow obstruction have mostly been evaluated in highly selected patient samples. Our objective was to evaluate the association between postbronchodilator lung function CRP and IL-6 in a randomly selected sample of the Icelandic population, 40 years and older, while adjusting for gender, age, smoking, and body weight.
Serum CRP and IL-6 values were measured among participants in the Burden of Obstructive Lung Disease (BOLD) study.
Of the 938 subjects invited a total of 403 men and 355 women participated (response rate 81%) in the study. Their mean age (±SD) was 57.7 (±12.7) years. Both CRP and IL-6 were independently related to lower FEV1 and FVC values. Individuals in the highest quartiles of CRP and IL-6 had a 7.5% and 3.9%, respectively, lower FEV1% than predicted after adjustment for smoking, age, and body weight. High CRP levels were more strongly related to lower FEV1 levels in men (−11.4%) than in women ( −0.4%).
In a random population-based sample both CRP and IL-6 were significantly related to lower spirometric values. The association with CRP was stronger in men than in women. This finding underscores the possible importance of systemic inflammation in irreversible airflow limitation.
Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation and accelerated decline in lung function.1 COPD is accompanied with signs of systemic inflammation.2,3 Circulating levels of several proinflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have been found to be elevated in the blood of selected patient populations with COPD.4,5 Patients with restrictive lung disease have also been found to have elevated blood levels of CRP.6
Elevated CRP and IL-6 levels are associated with an increased risk of future myocardial infarction and coronary artery disease,7,8 but there are only fewer studies on the relationship between IL-6 and COPD than CRP and COPD. A cohort of 148 COPD patients was followed for 2.91 years and IL-6 sputum concentration was found to rise by 9 pg/mL/year as FEV1 declined by 40.2 mL/year. Those patients who had more frequent exacerbations had a faster rise in sputum IL-6 over time.9 BMI had as strong an association with CRP levels as overweight (BMI 25–29.9), and obese subjects (BMI ≥ 30) were more likely to have elevated CRP than subjects of normal weight.10
We have previously,11 in a multicentre study on population-based cohorts of young to middle-aged subjects (age 28–56 years), shown that CRP is negatively associated with FEV1 and that this correlation was significantly larger in men than in women. Further, the rate of decline in lung function during the 8.3 years of follow-up was strongly correlated with high CRP levels among men. In general little is known about the relationship between airflow limitation, CRP and IL-6 in the middle-aged to older general population since most previous studies have been based on highly selected patient samples. Furthermore limited information is available on gender differences in the relationship between airflow limitation and markers of inflammation.
The aim of this study was to therefore evaluate the association between postbronchodilators FEV1, FVC, CRP and IL-6 in a randomly selected sample of the Icelandic population.
The Burden of Lung Disease Initiative (BOLD) is an international study on the prevalence of COPD that has recently been described in detail.12 The study was conducted in Reykjavik, Iceland, for over a period of 10 months from December 2004 to September 2005. The target population consisted of residents aged 40 years or older living in the capital of Reykjavik and the surrounding suburbs, an area with a population of about 180,000 individuals (compared to 300,000 for all of Iceland). Starting with the national registry, all age-eligible Icelandic citizens who were registered in Reykjavik and surrounding suburbs were identified. This sample consisted of 35,228 men and 38,163 women. Study participants (1000 subjects) were then selected using a simple random sample, not stratified by gender. After sampling it was found that 62 individuals did not fulfill the inclusion criteria. The final study group consisted of 938 individuals. After written informed consent was obtained subjects answered the standardized questionnaires administered by the trained interviewers, underwent spirometry tests, and a blood sample was obtained. The protocol was approved by the National Bioethics Committee of Iceland (04-080).
FEV1 and FVC values were obtained by spirometry. Testing was conducted with the participant in a sitting position wearing a nose clip and a disposable mouthpiece using the NDD Easy One™ (ndd Medizintechnik, Zurich, Switzerland) spirometer. Pre- and postbronchodilator tests were performed.12 In accordance with the BOLD protocol individuals who recently had a cold/upper respiratory infection were asked to participate later because of the effect on spirometry. BOLD uses the prediction equations for Caucasian adult men and women derived from the third United States National Health and Nutrition Examination Survey (NHANES III) as its primary reference equations for all participants.13
Blood was drawn from the antecubital vein of the seated subjects. Specimens were collected in SSTs from Greiner (Kremsmunster, Austria). Serum IL-6 concentrations were measured with enzyme-linked immunosorbent assays, using reagents obtained from IBL (Hamburg, Germany). The lower detection limit of the IL-6 assay was 0.074 pg/mL. CRP concentrations were measured on a Kone 30 analyser using a commercially available latex-enhanced immunoturbidimetric assay from Roche Diagnostic Systems (Mannheim, Germany). The lower detection limit of the assay was 0.1 mg/L.
All statistics were calculated with STATA software, version intercooled STATA 8.0 for Windows (Stata Corporation, College Station, Texas). Subjects were divided into four groups on the basis of the quartile distribution of the CRP values (<0.75, 0.75–1.27, 1.27–3.25, >3.25) and IL-6 values (<1.51, 1.51–2.82, 2.82–4.69 and >4.69 pg/mL). Log-transformed values of CRP were used to analyse the relationship between CRP and IL-6 and gender, pack year and BMI. Simple linear regression and the Chi-squared test were used in the univariate analyses, while logistic regression and multiple linear regression were used to perform multivariable analyses. Tests for interaction were carried out to detect the possible differences regarding the association between the inflammatory markers and the lung function between men and women as well as for BMI groups and smoking history. A p-value less than 0.05 was regarded as statistically significant.
Of the 938 subjects invited a total of 403 men and 355 women (47%) participated (response rate 81%) in the study. All except three, had acceptable postbronchodilator spirometry. Of the 180 non-responders, partial data were collected from 13 individuals, 85 refused to participate but answered a minimal data questionnaire, and 49 refused to participate at all. There was no significant difference between the responders and non-responders regarding age, smoking status or health. However, there was a significant difference in gender with proportionally more men participating (p = 0.01). The total response rate was 81%, ranging from 69% to 89% in different age groups, with the lowest among women aged 70 years and older and the highest among men aged 40–49 years.
Altogether, 746 blood samples were successfully analysed. A significant association was found between CRP and IL-6 (Fig. 1). Higher levels of CRP and IL-6 were associated with lower FEV1 and FVC values (Table 1).
The association between lower lung function and higher CRP remained significant after adjusting for age, sex, smoking, BMI and IL-6 (Fig. 2). Corresponding analyses with IL-6 showed that values in the highest IL-6 quartile were associated with lower FEV1 and FVC values (Fig. 3). CRP and IL-6 levels were both positively associated with BMI (Table 2).
CRP and IL-6 were also positively associated with pack years (p < 0.001 and p = 0.03, respectively). No significant associations were found between the inflammatory markers and age or sex.
A significant gender interaction was found in the association between CRP and FEV1 (p = 0.004) and CRP and FVC (p = 0.04) with significant associations in men but not in women (Table 3), whereas no corresponding interaction was found in relationship to IL-6. No significant interaction was found in relation to smoking or BMI.
Individuals with both IL-6 and CRP in the highest quartile (n = 79) had a lower FEV1 and FVC value − 10.5 (−15.7, −5.2)% and −10.3 (−14.6, −5.9)%, respectively, compared to those with IL-6 and CRP in the lowest quartiles after adjustment for age, sex, BMI, pack years and current smoking.
The main finding of this study was that higher levels of circulating CRP and IL-6 were independently related to lower FEV1 and FVC values in a population-based sample of Icelanders who were 40 years and older. There was a gender difference in that the relationship between FEV1 and CRP was stronger in men than in women. This has not been shown in previous studies.
In our study CRP and IL-6 were both positively associated with BMI and pack years. We have previously reported such a strong association between CRP, smoking and BMI in multicentre epidemiological study based on young and middle-aged adults from Uppsala, Reykjavik and Tartu.14 Shaaban et al. also reported similar findings from a general population in France.15 This was also true when they followed the group longitudinally for over a period of 8.5 years. In our study a significant association was found between CRP and IL-6 levels. This is not surprising given how closely these markers are associated with the inflammatory responses of the body and the fact that CRP is produced by hepatocytes under the control of IL-6.16
Higher levels of CRP and IL-6 were associated with lower FEV1 and FVC values. Such association has been described before with FEV1.2,4,5 A report by Mannino et al. showed that elevation in CRP, both in patients with obstructive and restrictive lung diseases, had an association with FVC.6 A study by Engstrom et al. also found a relationship with FVC.17 The association between lower lung function and higher CRP remained significant after adjusting for age, sex, smoking, BMI and IL-6. These results are similar to many other studies, both based on patient populations with COPD and general populations where COPD has been identified by spirometric values.2,4–6,11 In our study IL-6 was significantly related both to proportionally lower FEV1 and FVC values, and this association was still significant after adjustment for age and BMI. IL-6 has been shown to be higher in COPD patients in other studies2 and related to reduced lung function. No gender differences were found in relationship to IL-6.
We found a significant gender difference in the association between CRP, FEV1 and FVC, with gender being significant in men and not in women. This is a finding which we have also noted in a younger–middle-aged cohort.11 Hormonal differences might explain the gender difference as a study by Nakhai Pour et al. showed that levels of estradiol were significantly associated with CRP among middle-aged and older men.18 Van Pottelbergh et al., however, found no correlation between testosterone or estradiol levels and CRP in healthy middle-aged men19 and Karadag et al. found no relationship between testosterone or estradiol and IL-6 in patients with COPD.20 Weight-related or smoking-related effects are also other possibilities that could explain gender differences.21 A gender difference in the association between IL-6, FEV1 and FVC was not found. This might have several explanations. This might be due to different fat distribution between males and females or due to genetic differences.16
Individuals with both CRP and IL-6 in the highest quartile had 10.3% lower FEV1 and FVC values compared to those in the lowest quartiles after adjustment for age, sex, BMI, pack years and current smoking. A study based on The Framingham Heart Study population found that a 1-SD higher concentration of CRP was associated with an FEV1 that was 46 mL lower.4 In our study individuals with IL-6 in the highest quartile had FEV1 and FVC values that were 10.5% lower than in those with IL-6 in the lowest quartiles after adjustment for age, sex, BMI, pack years and current smoking. The Framingham Heart Study found that a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV1 and a borderline 15% higher odds of COPD.4
The present study has several advantages. Firstly, subjects were recruited from a well-defined population, represented a single ethnic group and were aged 40 years and older. The high participation rate should reflect the country’s general population. Approximately the same number of men and women participated. Minimal differences were found between the responders and the non-responders. An international well-standardized protocol was used with excellent training of staff.12 All spirometry testings were sent to a quality control centre.12 Since the air pollution in Iceland is very low22 it is fairly easy to explore the effects of cigarette smoke on lungs. Reykjavik also has low levels of airborne allergens23 and no major industries except for an aluminium smelting plant approximately 20 km south-west of the city centre. However, previous studies have shown that both active and passive cigarette smoke exposures in Iceland have been among the highest in northern Europe,24 and worldwide, Icelandic women lead in the prevalence of “ever smoking”.12
There are several limitations to this study. A single IL-6 and CRP measurement per person was done, which may not accurately reflect long-term inflammation status. However, the substantial biological variability of CRP levels was reduced by using a high-sensitivity method for CRP analysis. The fact that we did not exclude subjects with a CRP level > 10 mg/L might have influenced the results. However, only 16 individuals of a total of 746 had CRP levels higher than 10 mg/L and the highest value measured was under 20 mg/L, probably because only non-infected subjects were investigated. The study was performed during a 10-month period. Normally there is not much seasonal variation in CRP and IL-6 levels16 and no significant difference was found in CRP or IL-6 levels between subjects examined in the darker or lighter part of the year (data not shown). Respiratory infection could also have influenced our results but the examination was delayed until recovery, if the study subject had symptoms/signs of infection. This should have minimized the effects of infection or other causes of exacerbations on CRP and IL-6 values. Obesity and smoking are associated with signs of systemic inflammation.5,7,8 We therefore adjusted for these factors in our study. The effects of these factors should therefore be minimal when evaluating the relationship between decreased lung function and markers of systemic inflammation.
The relationship between markers of inflammation and local intrapulmonary processes that result in chronic airflow obstruction is not well understood.2 Whether the systemic inflammation contributes to the development of irreversible airflow obstruction or is an epiphenomenon is unknown. We did not control for cardiovascular risk factors in our study. Therefore we cannot exclude the possibility that unknown cardiovascular risk factors might have caused some changes in IL-6 and CRP.25
In this population-based study of Icelanders aged 40 years and older we found that higher levels of circulating CRP and IL-6 were independently related to lower FEV1 and FVC values. There was a gender difference in that the relationship between FEV1 and CRP was stronger in men than in women. This has not been shown before. These results warrant further studies.
The authors thank all those who participated in the BOLD study and coworkers (particularly Lovisa Gudmundsdottir, Kristin Bara Jorundsdottir and Sigrun Gudmundsdottir). This study was funded by the Landspitali University Science Fund, Astra Zeneca in Iceland and GlaxoSmithKline in Iceland.
Conflicts of interest There are no conflict of interests for any of the authors.