Plasma levels of inflammatory C-reactive protein and interleukin-6 predict outcome in elderly patients with stroke.

Abstract

To the Editor: It has been suggested that the acute inflammatory response to tissue injury, which is marked by elevated levels of acute-phase proteins such as fibrinogen and C-reactive protein (CRP) and by leukocytosis, may have an important causal role in stroke.1 Elevated serum CRP levels have been reported to be associated with a worse prognosis in patients with cardiovascular disease.2 In these patients, high plasma levels of CRP, reflecting the increased inflammatory activity, also predicted a rapid progression of the underlying disease.3, 4 Recently, it has been suggested that elevated CRP levels independently predict the risk of future stroke and transient ischemic attack in the elderly.5 Serum levels of interleukin-6 (IL-6) are predictive of cardiovascular risk and are correlated with the levels of CRP.6 IL-6 is elevated in the cerebrospinal fluid of patients with acute stroke, but the predictive relative importance of CRP and IL-6 levels during the early phase of hospitalization in elderly patients with ischemic stroke has never been fully elucidated. Between January and December 2000 we studied a population of 647 consecutive elderly patients (aged≥65) admitted to our unit with ischemic stroke documented using computed tomography (CT), presence of significant carotid atherosclerosis (>50% stenosis of common carotid arterial or internal carotid arterial using ultrasound), absence of atrial fibrillation, and refusal to undergo thromboendarterectomy. Patients receiving thrombolytics and those with chronic or acute inflammatory or infectious disease (of these, infective endocarditis was excluded using medical examination and by echocardiogram) were excluded. Clinical features of study patients are reported in Table 1. CRP and IL-6 plasma levels were measured within 12 hours of admission, on Day 3 during hospitalization, and at discharge. Patients were evaluated at 3-month intervals during a mean ± standard deviation follow-up of 16±5 months. At each visit, a full medical examination was performed, and occurrence of any event was noted. Unfavorable outcome was defined as cardiac death, death related to a cerebral ischemic event, new cerebrovascular event, or myocardial infarct. The in-hospital mortality was 6%. During follow-up, overall mortality was 15%, and another cerebrovascular event occurred in 12% of patients. In addition, 16 patients were hospitalized because of unstable angina pectoris, 13 had an ischemic stroke, 12 suffered an acute myocardial infarction, and five had a transient ischemic attack. No significant difference in plasma levels of IL-6 and CRP were detected between admission and Day 3. Patients with in-hospital events had significantly higher CRP and IL-6 levels at admission than patients without events (3.8±1.1 vs 1.9±0.9 mg/L, P<.01 and 13.8±3.4 vs 6.3±2.1 pg/mL, P<.01, respectively). Also, CRP and IL-6 levels at admission were significantly higher in patients with a new event within 3 months of discharge than in patients without an event (3.6±1.3 vs 1.1±0.7 mg/L, P<.01 and 14.2±3.7 vs 5.4±1.6 pg/mL, P<.01, respectively). In a multivariate analysis, baseline CRP and IL-6 levels were predictors of future in-hospital and 3-month future cerebrovascular events, whereas high CRP and IL-6 levels at baseline were not associated with a poor 1-year prognosis. Elevated CRP levels were associated with an unfavorable outcome only when IL-6 levels were also elevated. In a stepwise multivariate analysis, IL-6 levels were stronger predictors of outcome than CRP. These results show that CRP and IL-6 measured at admission in patients with an ischemic stroke are predictive of future cerebrovascular events in the medium term (3 months) but not in the long term (1 year). These findings are in agreement with the observations of one study that found significantly elevated IL-6 in patients after stroke and with the finding that IL-6 is correlated with CRP.7 Elevated IL-6 and CRP concentrations are present in patients with large established infarcts on CT and may reflect the degree of stroke severity, correlating with the degree of inflammation directly consequent to cerebral infarction, or may be related to the degree of carotid vascular inflammation. These findings are consistent with a role for inflammation in acute ischemic stroke, as well as with the hypothesis that elevated CRP and IL-6 may predict future cardiovascular mortality. If increased CRP and IL-6 shortly after stroke is confirmed as an index of subsequent cardiovascular risk, these patients could be targeted for more aggressive conventional treatment or novel therapies intended to stabilize atherosclerotic plaque.