Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP).
Objective: To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD.
Methods: We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study.
Measurements and Main Results: We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus ⩽ 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV1% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0–2.0) and 2.2 (1.2–3.9) in individuals with baseline CRP > 3 mg/L versus ⩽ 3 mg/L. After close matching for FEV1% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV1% predicted of less than 50.
Conclusions: CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.
C-reactive protein (CRP) has been shown to be a marker of inflammation in atherosclerosis and levels of CRP correlate with the degree of pulmonary inflammation in stable COPD.
Serum C-reactive protein is a strong long-term predictor of clinical COPD outcomes in individuals with airway obstruction.
The most commonly used acute-phase reactant in clinical situations, C-reactive protein (CRP), binds bacteria (10, 11), oxidized lipids (12, 13), and apoptotic cells (13, 14) and facilitates their clearance via the innate immune system. Slightly increased serum CRP levels have been shown to associate with presence of inflammation in atherosclerosis and with increased risk of coronary heart disease and myocardial infarction (15). Mounting evidence now suggests that increased serum CRP levels also associate with lung inflammation in stable COPD (5, 16–18). It is therefore possible that serum CRP as a systemic marker of ongoing lung inflammation could be used as a predictor of future COPD outcomes.
In a cohort study, we tested the hypothesis that increased concentrations of serum CRP predict increased risk of hospitalization and death from COPD in individuals with airway obstruction. For this purpose, we measured lung function in 9,259 individuals from a general population sample and determined baseline serum CRP in individuals with the presence of airway obstruction. During a median follow-up period of 8 yr, we recorded COPD admissions and deaths as outcomes.
Subjects participated in the 1991–1994 examination of the Copenhagen City Heart Study, a prospective epidemiologic study initiated in 1976–1978 (19–21). Participants aged 20 yr and older were selected randomly after age stratification into 5-yr age groups from residents of central Copenhagen. Of the 17,180 individuals invited, 10,135 participated and 9,259 gave blood. Of these, 1,561 had airway obstruction defined as FEV1/FVC of less than 0.7, and 1,302 had never been hospitalized for COPD or asthma before the 1991–1994 examination. More than 99% were white and of Danish descent. All participants gave written, informed consent, and Herlev University Hospital and the ethics committee for Copenhagen and Frederiksberg approved the study (Study no. 100.2039/91).
Participants reported whether they were current smokers, ex-smokers, or never-smokers, and all current smokers provided information on the type and daily amount of tobacco they consumed. Information on hospitalizations due to COPD (International Classification of Diseases, 8th revision [ICD-8]: 491–492; ICD-10: J41–J44) was drawn from the Danish National Hospital Discharge Register from May 1, 1976, through December 31, 2000; hospital data before CRP measurements were used to exclude individuals who already had a diagnosis of COPD or asthma (ICD-8: 493; ICD-10: J45–J46). Data on deaths due to COPD were drawn from the Danish National Register of Causes of Death (ICD-8: 491–492; ICD-10: J41–J44) from April 1, 1992, to December 31, 1999; individuals with asthma (ICD-8: 493; ICD-10: J45–J46) as a contributory cause of death on the death certificate were excluded. We followed the COPD definition used in previous studies of Danish patients with COPD (22). Three COPD hospitalizations and no COPD deaths were identified by adding ICD-8 490 to our COPD definition, and including these cases in the analysis did not change the results presented. The ICD-8 496 code was never implemented in the Danish ICD-8 version. Written approval for data linkage was obtained from the Danish national registers. The ICD-8 was used until the end of 1993 in Denmark, followed by the ICD-10; the ICD-9 was never implemented in Denmark. Twelve and six of the study participants died of COPD in 1993 (ICD-8) and 1994 (ICD-10), respectively. Of the 83 deaths with COPD listed on the death certificate, 57 (69%) had COPD as the major cause of death; 12 (14%) had other causes (ICD-8 or -10 codes 154.1, A169, C159, D696, E107, C619, C809, K265, K519, R989, R999, W190); 7 (8%) had lung cancer (162.1, C349); and 7 (8%) had cardiovascular disease (I219, I249, I350, I519, I709, I710), with COPD as a contributory cause of death.
Serum CRP was measured by high-sensitivity CRP assay (Dade Behring Diagnostica, Rødovre, Denmark). FEV1 and FVC were measured with a dry wedge spirometer (Vitalograph, Maidenhead, UK). The highest set of three sets of FEV1 and FVC measurements was used as percentage of predicted value using internally derived reference values based on a subsample of healthy never-smokers (23).
When relating CRP to outcomes (hospital admission and death), baseline CRP concentration was categorized using two cut-points, 1 and 3 mg/L. These cut-points were used rather than quartiles, because stratifying into smaller groups may increase the risk of spurious findings, and because these cut-points are simple and clinically useful and have been used previously in cardiovascular medicine (24).
Statistical analysis was performed with SPSS 14.0 for Windows (SPSS, Inc., Chicago, IL); p < 0.05 on a two-sided test was considered significant. Pearson's χ2 test, Mann-Whitney U test, or Student's t test were used for two-group comparisons, depending on data distribution. The cumulative incidences of COPD outcomes as a function of age were compared using the log-rank test. Cox regression analysis was used to examine time to COPD hospitalization or death using hazard ratios and 95% confidence intervals; the multiple adjusted model included sex, age (in deciles), FEV1% predicted (in deciles), tobacco consumption (in deciles), and ischemic heart disease (ICD-8: 410–414; or ICD-10: I20–I25); adjusting for deciles implies categorical, as opposed to quantitative, variables (nine variables in the regression model). For each case of COPD hospitalization, COPD death, and death by any cause, controls in the same decile of FEV1% predicted were selected using a computer matching program for SPSS. After matching, baseline CRP concentration (logarithmically transformed) was estimated by analysis of variance (ANOVA), adjusting for sex, age (in deciles), tobacco consumption (in deciles), and ischemic heart disease. Estimated absolute risks for COPD outcomes were calculated using the regression coefficients from a Poisson regression model with FEV1% predicted, tobacco consumption, age, and CRP. Absolute risks are presented as estimated incidence rates (events/10 yr) in percentages. The dependent variables for the Poisson regressions are number of COPD hospitalizations or COPD deaths during the subsequent 10 yr.
A total of 1,302 individuals with airway obstruction defined as FEV1/FVC less than 0.7 were included in the study; these individuals had not previously been diagnosed with COPD in the Danish National Hospital Discharge Register. During a median duration of 8 yr follow-up, 185 individuals (14%) were hospitalized due to COPD and 83 (6%) died of COPD. Of the 83 COPD deaths, 41 (49%) were preceded by a hospital admission for COPD. The baseline characteristics of the participants in whom a COPD outcome subsequently developed are shown in Table 1. As expected, participants who had any COPD outcome had lower FEV1% predicted at baseline than those who remained free of COPD outcomes, and they were more likely to be older and have a higher daily tobacco use.
COPD Outcomes during Follow-up | |||||||
|---|---|---|---|---|---|---|---|
| None | Any | Hospitalization | Death | ||||
| Female/male, n | 490/604 | 107/101 | 102/83§ | 38/45 | |||
| Age, yr | 66 (58–73) | 68 (63–73)† | 68 (63–72) | 70 (64–75)‡ | |||
| FEV1, % predicted | 74 ± 19 | 57 ± 19‡ | 57 ± 19‡ | 49 ± 19‡ | |||
| Tobacco consumption, g/d | 11 (0–20) | 15 (4–20)§ | 15 (6–20)§ | 14 (0–20) | |||
| Ischemic heart disease* | 148 (14%) | 37 (18%) | 35 (19%) | 13 (16%) | |||
| CRP, mg/L | 2.3 (1.0–4.9) | 3.4 (1.7–7.5)‡ | 3.3 (1.6–7.4)‡ | 4.3 (2.1–7.8)‡ | |||
Baseline serum levels of CRP were higher in individuals who subsequently had a COPD outcome than in those who did not (Table 1). The difference was largest for those who subsequently died of COPD, 4.3 versus 2.3 mg/L (p < 0.001). The prevalence of ischemic heart disease did not differ significantly by COPD outcome status (Table 1; χ2: p = 0.27). The cumulative incidence of COPD hospitalization and COPD death was higher in those with CRP of more than 3 mg/L versus CRP of 3 mg/L or less (Figure 1; log-rank: p < 0.001 and p < 0.001, respectively). The equivalent cumulative incidences overall also increased with increasing baseline CRP concentration from less than 1 mg/L to 1–3 mg/L to greater than 3 mg/L; however, the cumulative incidence of COPD outcomes for CRP of 1–3 mg/L versus less than 1 mg/L did not differ significantly (p = 0.19 and p = 0.07, respectively).
Figure 1. Cumulative incidence of chronic obstructive pulmonary disease (COPD) events according to baseline serum C-reactive protein (CRP) levels. Cumulative incidences of COPD hospitalization and death were increased in individuals with baseline CRP > 3 mg/L versus those with baseline CRP ⩽ 3 mg/L.
[More] [Minimize]To assess the independent predictive value of baseline CRP of more than 3 mg/L on COPD hospitalization and death, we adjusted our analyses according to potential confounders. Before adjustment, the crude hazard ratios for hospitalization and death due to COPD were increased at 1.7 (95% confidence interval, 1.2–2.4) and 2.7 (1.6–4.7), respectively, in individuals with baseline CRP of more than 3 versus 3 mg/L or less (Table 2). After adjusting for age, the equivalent hazard ratios for COPD hospitalization and COPD death were 1.6 (1.2–2.3) and 2.5 (1.5–4.4), respectively. In a multifactorial analysis including sex, age, FEV1% predicted, tobacco consumption, and ischemic heart disease, the equivalent hazard ratios for COPD hospitalization and COPD death were increased at 1.4 (1.0–2.0) and 2.2 (1.2–3.9), respectively.
CRP Concentration > 3 mg/L vs. ⩽ 3 mg/L | |||||||
|---|---|---|---|---|---|---|---|
| Events (n) | Crude | Age* | Multiple† | ||||
| COPD hospitalization | 139 | 1.7 (1.2–2.4) | 1.6 (1.2–2.3) | 1.4 (1.0–2.0) | |||
| COPD death | 58 | 2.7 (1.6–4.7) | 2.5 (1.5–4.4) | 2.2 (1.2–3.9) | |||
| All-cause mortality | 329 | 1.8 (1.4–2.2) | 1.7 (1.4–2.1) | 1.4 (1.1–1.8) | |||
Increased serum CRP may also increase the risk of all-cause mortality in individuals with pulmonary dysfunction (25). The unadjusted hazard ratio for all-cause mortality was increased at 1.8 (1.4–2.2) in individuals with baseline CRP of more than 3 mg/L versus those with CRP of 3 mg/L or less (Table 2). In an age-adjusted and multifactorial analysis, the equivalent hazard ratios for all-cause mortality were increased at 1.7 (1.4–2.1) and 1.4 (1.1–1.8), respectively.
FEV1% predicted is the most important predictor of future COPD outcomes. To ensure that CRP predicted COPD outcomes independently of FEV1, we also performed cross-sectional analyses with matching for FEV1% predicted. In an analysis matching for FEV1% predicted and adjustment for sex, age, tobacco consumption, and ischemic heart disease, baseline CRP was on average increased by 1.2 mg/L in those who were hospitalized for COPD (ANOVA: p = 0.002), by 4.1 mg/L in those who died of COPD (p = 0.001), and by 1.9 mg/L in those who died of any cause (p < 0.001).
The lowest absolute 10-yr risks for COPD hospitalization and death were 5.7 and 1.0%, respectively, among individuals with CRP of 3 mg/L or less, age of 70 yr or younger, tobacco consumption of 15 g/d or less, and FEV1% predicted above 79% (Figure 2). Absolute risk increased with increasing serum CRP, increasing tobacco consumption, increasing age, and decreasing FEV1% predicted. The highest absolute 10-yr risks for COPD hospitalization and death were, respectively, 54 and 57% among individuals with CRP more than 3 mg/L, age older than 70 yr, tobacco consumption more than 15 g/d, and FEV1% predicted less than 50.
Figure 2. Absolute 10-yr risks for chronic obstructive pulmonary disease (COPD) hospitalization and COPD death according to FEV1% predicted, tobacco consumption, age, and serum C-reactive protein (CRP). The dependent variables for the Poisson regressions are number of COPD hospitalizations or COPD deaths during the subsequent 10 yr. The highest absolute 10-yr risks for COPD hospitalization and death—54 and 57%—were found among individuals with CRP > 3 mg/L, age > 70 yr, tobacco consumption > 15 g/d, and FEV1% predicted less than 50.
[More] [Minimize]This 8-yr follow-up study of a large and ethnically homogenous population with airway obstruction shows that increased serum CRP is a strong long-term predictor of COPD hospitalization and death, independent of smoking and lung function. The results expand the observations of increased CRP levels in stable COPD (5, 17, 18, 26). Gan and colleagues aggregated data from five cross-sectional studies and estimated an average mean increase in serum CRP of 1.85 mg/L in individuals with stable COPD (5). Increased CRP has also been associated with all-cause mortality in patients with mild to moderate COPD, reduced lung function, and greater FEV1 decline (25, 27–29). Our data now indicate that increased CRP predicts clinical COPD outcomes in individuals with airway obstruction during 8 yr of follow-up.
Serum CRP at baseline was increased the most in those who subsequently died of COPD, and CRP was also a stronger predictor of COPD mortality than of COPD hospitalization. Consistent with this, elevated serum CRP has been found to mark metabolic and functional impairment in advanced COPD (30, 31). CRP correlates with other inflammatory markers, but Broekhuizen and colleagues have also shown that it correlates with a reduced exercise capacity, a reduced 6-min-walk distance, and health-related quality of life (31). In addition, Sin and Man showed that levels of CRP were predictive of adverse cardiac events in patients with COPD in the NHANES (National Health and Nutrition Examination) studies, measured as subsequent raised Cardiac Infarction Injury Score based on ECG readings (32). Our findings differ from these because we looked at more directly related COPD endpoints, the predictive value of CRP was not driven by cardiac events, and the effect of CRP seemed less dependent of level of lung function.
In the literature, there are strong arguments for CRP increasing thrombotic risk and cardiovascular deaths (15). However, this could not explain the current findings, because there was no higher prevalence of ischemic heart disease in participants who had a COPD outcome than in those free of an event (Table 1). Also, cardiovascular disease tended to occur less frequently as a contributing cause of death among those who died of COPD than among those who died of other causes (39 vs. 47%; χ2: p = 0.19). Hence, in individuals with airway obstruction, CRP seems a strong predictor of COPD outcomes independent of cardiovascular events.
FEV1% predicted is the most important predictor of future clinical COPD outcomes. After adjustment with or without matching for FEV1% predicted, serum CRP remained a significant predictor of clinical COPD outcomes adding to the prognostic value of FEV1 in predicting COPD. This corroborates with the idea that airflow limitation and airway inflammation are separate and independent factors in the pathophysiology of COPD (33), and suggests that serum CRP predicts future COPD in individuals with airway obstruction independent of lung function.
In the lung, CRP has protective functions in innate immune responses against bacteria and apoptotic cells. CRP enters the lung from plasma and is primarily produced by hepatocytes in response to IL-6 stimulation. Activated epithelial cells and increased numbers of alveolar macrophages and other inflammatory cells in COPD may release IL-6 into the circulation (34–36). This stimulates an acute-phase response and increases the level of plasma CRP. Consistent with our CRP data and a potential role for IL-6 in COPD pathogenesis, two other IL-6–regulated acute-phase reactants (fibrinogen and α1-antitrypsin) are also associated with features of COPD (37, 38). In further support of a role for IL-6 in COPD development, studies indicate the following: (1) IL-6 increases the number of lung CD4 cells, CD8 cells, B cells, neutrophils, and macrophages (34–36, 39–44), consistent with the changes observed in human COPD pathology (45); (2) overexpression of IL-6 leads to emphysema-like airspace enlargement, peribronchiolar collections of mononuclear cells, thickening of airway walls, subepithelial fibrosis, and airway hyperresponsiveness (39, 40, 46); (3) intravenous IL-6 injections into rats lead to respiratory and peripheral skeletal muscle wasting (47); and (4) lung injury is attenuated by the absence of IL-6 after exposing animals to ozone (44, 48).
Plasma CRP may therefore be associated with IL-6–related processes in the airways that, over time, lead to progression of COPD with severe clinical implications. Further studies using rigorous molecular biological methodology are required to determine specifically any potential roles of IL-6 in COPD pathology. Plasma CRP may not only be used to assess inflammation during the course of COPD but may also be useful as a marker to monitor inflammation during COPD treatment, as increased serum CRP in stable COPD seems to be reduced by treatment with an inhaled corticosteroid (49).
Because we studied a sample of individuals with airway obstruction from the adult Danish general population, generalizability of our data to other populations or races may potentially be constrained. Bias caused by investigators' knowledge of disease or risk factor status is unlikely, because we measured CRP and other basic characteristics at baseline and followed the study participants prospectively.
Another important implication of this study is that we may now calculate 10-yr risks for death or hospitalization in patients with COPD on what would appear to be sound basis, as is done in cardiology for myocardial infarction and cardiac death. This may be useful when counseling patients with COPD in the clinical setting. In conclusion, serum CRP is a strong long-term predictor of future COPD outcomes in individuals with airway obstruction.
The authors thank Hanne Damm for expert technical assistance.
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