In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.
The objective of this study was to determine whether: (a) markers of acute inflammation (white cell count, glucose, interleukin-6, C-reactive protein, and fibrinogen) are associated with poor outcome after stroke and (b) the addition of markers to previously validated prognostic models improves prediction of poor outcome.
Methods and Findings
We prospectively recruited patients between 2002 and 2005. Clinicians assessed patients and drew blood for inflammatory markers. Patients were followed up by postal questionnaire for poor outcome (a score of>2 on the modified Rankin Scale) and death through the General Register Office (Scotland) at 6 mo. We performed a systematic review of the literature and meta-analysis of the association between interleukin-6 and poor outcome after stroke to place our study in the context of previous research. We recruited 844 patients; mortality data were available in 844 (100%) and functional outcome in 750 (89%). After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9–5.0); C-reactive protein, 1.9 (95% CI: 1.2–3.1); fibrinogen, 1.5 (95% CI: 1.0–2.36); white cell count, 2.1 (95% CI: 1.3–3.4); and glucose 1.3 (95% CI: 0.8–2.1). The results for interleukin-6 were similar to other studies. However, the addition of inflammatory marker levels to validated prognostic models did not materially improve model discrimination, calibration, or reclassification for prediction of poor outcome after stroke.
Raised levels of markers of the acute inflammatory response after stroke are associated with poor outcomes. However, the addition of these markers to a previously validated stroke prognostic model did not improve the prediction of poor outcome. Whether inflammatory markers are useful in prediction of recurrent stroke or other vascular events is a separate question, which requires further study.
Please see later in the article for the Editors' Summary
Every year, 15 million people have a stroke. In the US alone, someone has a stroke every 40 seconds and someone dies from a stroke every 3–4 minutes. Stroke occurs when the blood supply to the brain is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek medical assistance immediately because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Many people are left with permanent disabilities after a stroke. An accurate way to predict the likely long-term outcome (prognosis) for individual patients would help clinicians manage their patients and help relatives and patients come to terms with their changed circumstances. Clinicians can get some idea of their patients' likely outcomes by assessing six simple clinical variables. These include the ability to lift both arms and awareness of the present situation. But could the inclusion of additional variables improve the predictive power of this simple prognostic model? There is some evidence that high levels in the blood of inflammatory markers (for example, interleukin-6 and C-reactive protein) are associated with poor outcomes after stroke—inflammation is the body's response to infection and to damage. In this prospective cohort study, the researchers investigate whether inflammatory markers are associated with poor outcome after stroke and whether the addition of these markers to the six-variable prognostic model improves its predictive power. Prospective cohort studies enroll a group of participants and follow their subsequent progress.
What Did the Researchers Do and Find?
The researchers recruited 844 patients who had had a stroke (mainly mild ischemic strokes) in Edinburgh. Each patient was assessed soon after the stroke by a clinician and blood was taken for the measurement of inflammatory markers. Six months after the stroke, the patient or their relatives completed a postal questionnaire that assessed their progress. Information about patient deaths was obtained from the General Register Office for Scotland. Dependency on others for the activities of daily life or dying was recorded as a poor outcome. In their statistical analysis of these data, the researchers found that raised levels of several inflammatory markers increased the likelihood of a poor outcome. For example, after allowing for age and other factors, individuals with interleukin-6 levels in the upper third of the measured range were three times as likely to have a poor outcome as patients with interleukin-6 levels in the bottom third of the range. A systematic search of the literature revealed that previous studies that had looked at the potential association between interleukin-6 levels and outcome after stroke had found similar results. Finally, the researchers found that the addition of inflammatory marker levels to the six-variable prognostic model did not substantially improve its ability to predict outcome after stroke for this cohort of patients.
What Do These Findings Mean?
These findings provide additional support for the idea that increased levels of inflammatory markers are associated with a poor outcome after stroke. However, because patients with infections were not excluded from the study, infection may be responsible for part of the observed association. Importantly, these findings also show that although the inclusion of inflammatory markers in the six variable prognostic model slightly improves its ability to predict outcome, the magnitude of this improvement is too small to warrant the use of these markers in routine practice. Whether the measurement of inflammatory markers might be useful in the prediction of recurrent stroke—at least a quarter of people who survive a stroke will have another one within 5 years—requires further study.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000145.
This study is further discussed in a PLoS Medicine Perspective by Len Kritharides
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation (in English and Spanish)
The Internet Stroke Center provides detailed information about stroke for patients, families and health professionals (in English and Spanish)
The UK National Health Service also provides information for patients and their families about stroke (in several languages)
MedlinePlus provides links to further resources and advice about stroke (in English and Spanish)
The six simple variable model for prediction of death or disability after stroke is available here: http://dcnapp1.dcn.ed.ac.uk/scope/