Leukocyte count predicts outcome after ischemic stroke: The Northern Manhattan Stroke Study

Leukocyte Count Predicts Outcome After Ischemic Stroke: The Northern Manhattan Stroke Study Mitchell S. V. Elkind, MD, MS,*,† Jianfeng Cheng, MD, MS,‡ Tanja Rundek, MD, PhD,* Bernadette Boden-Albala, MPH,†,§ and Ralph L. Sacco, MD, MS*,†,储

Leukocyte counts predict incident cardiovascular disease, but little data are available on the relationship of leukocyte count to outcome after ischemic stroke. We hypothesized that leukocyte count at the time of incident ischemic stroke is associated with prognosis. Patients with first ischemic stroke were prospectively followed for 5 years for the occurrence of recurrent stroke, myocardial infarction (MI), or death. Cox proportional hazard models were constructed to estimate hazard ratios and 95% confidence intervals (CIs) for the effect of leukocyte count on outcomes after adjusting for other risk factors. Ischemic stroke patients (n ⫽ 655) were evaluated (mean age, 69.7 ⫾ 12.7 years; 45% men; 51% Hispanic, 28% black, and 19% white). Seventy percent of samples were drawn within 24 hours of stroke. Mean leukocyte count was 9.1 ⫾ 4.7 ⫻ 109/L. Leukocyte count was a significant independent predictor of the 30-day risk of recurrent stroke, MI, or death after adjusting for age, sex, race/ethnicity, other risk factors, and stroke severity (adjusted hazard ratio per unit increase in leukocyte count, 1.07; 95% CI, 1.00 to 1.13). Leukocyte count was also a significant independent predictor of outcome events over 5 years (adjusted hazard ratio per unit increase in leukocyte count, 1.04; 95% CI, 1.00 to 1.07). Our findings indicate that elevated leukocyte count at the time of ischemic stroke predicts future recurrent stroke, MI, or death. Acute infectious complications of stroke or underlying inflammation could account for this association. Key Words: Cerebral infarction—leukocytes—mortality—prognosis—stroke. © 2004 by National Stroke Association

From the *Department of Neurology, College of Physicians and Surgeons, Columbia University, and the Columbia University Medical Center of New York-Presbyterian Hospital, New York, NY; †Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY; ‡Division of Biostatistics, and §Division of Sociomedical Sciences, Joseph P. Mailman School of Public Health, Columbia University, New York, NY; and 储Division of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University, New York, NY. Received July 1, 2004; accepted July 1, 2004. Supported by grants from the Columbia University Office of Clinical Trials (pilot grant; M.S.V.E.), National Institute of Neurolog-

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ical Disorders and Stroke (R01 NS 27517 [R.L.S.]; K2342912 [M.S.V.E.]), the General Clinical Research Center (2 M01 RR00645), and Centers for Disease Control Cooperative Agreement (M.S.V.E.). Address reprint requests to Mitchell S. Elkind, MD, Neurological Institute, 710 West 168th Street, New York, NY 10032. E-mail: [email protected]. 1052-3057/$—see front matter © 2004 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2004.07.004

Journal of Stroke and Cerebrovascular Diseases, Vol. 13, No. 5 (September-October), 2004: pp 220-227

LEUKOCYTE COUNT AND STROKE PROGNOSIS 1-6

Elevated counts of leukocytes and other inflammatory markers, including interleukin 6 (IL-6),7 C-reactive protein,8-10 and soluble intercellular adhesion molecules,11,12 predict incident cardiovascular events. Elevated levels of these and other inflammatory markers at the time of myocardial infarction (MI) are associated with poor prognosis.13-17 These findings are thought to reflect the importance of inflammatory processes in the pathogenesis of atherosclerotic coronary artery disease.18 The role of inflammatory mediators in causing stroke is less well substantiated,19-21 and the relationship of leukocyte count to prognosis after stroke has been studied only infrequently.22 Elevated leukocyte count after stroke could be associated with a worse prognosis because of concurrent infection, which may itself increase risk of death or another adverse event. Pneumonia, urinary tract infections, decubitus ulcers, and other infections could all contribute to poor outcome after stroke.23 Noninfectious complications, such as deep venous thrombosis, which may also be associated with elevated leukocyte levels, may also contribute to a poor outcome.23 Alternatively, elevated leukocyte levels could be another marker of the underlying atherosclerotic burden of patients, making them more likely to have further cardiovascular events. Studies, including our own, have found that leukocyte count24 and tumor necrosis factor receptor levels are independently associated with carotid plaque thickness crosssectionally25 and progression of carotid intima-media thickness over time.26 We hypothesized that leukocyte count at the time of ischemic stroke is associated with an increased risk of recurrent stroke, MI, or death among an elderly, urban, multiethnic population.

Patients and Methods The Northern Manhattan Stroke Study (NOMASS) includes a population-based incident ischemic stroke follow-up study designed to determine predictors of stroke recurrence and prognosis in a multiethnic, urban population. Northern Manhattan consists of the area north of 145th Street, south of 218th Street, bordered on the west by the Hudson River, and on the east by the Harlem River. In 1990, nearly 260,000 people lived in the community, with 40% over age 39 and a racial/ethnic mixture consisting of 20% black, 63% Hispanic, and 15% white residents.27 The Hispanic population enrolled in NOMASS is representative of the underlying Caribbean Hispanic community in New York City. This population is primarily Dominican (62%), with an additional 14% Puerto Rican, 12% Cuban, and 12% reporting origins from various Caribbean islands and South and Central America.28

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Selection of the NOMASS Cohort The methods of patient identification and enrollment have been described previously.29,30 Briefly, stroke patients were enrolled if they (1) were diagnosed with a first stroke; (2) were over age 40, and (3) resided in Northern Manhattan for ⱖ3 months in a household with a telephone. For this analysis, only ischemic stroke cases were included. More than 80% of patients with acute ischemic stroke in northern Manhattan are hospitalized at the Columbia University Medical Center (CUMC). Subjects hospitalized at other local hospitals were identified through active surveillance of admissions to those hospitals and through agreements with local physicians. Approximately 5% of incident ischemic stroke in northern Manhattan are not hospitalized.30 Evaluation of patients was performed at the hospital; those subjects either not hospitalized or hospitalized elsewhere were evaluated in the outpatient research clinic. The study was approved by the Institutional Review Board at CUMC. All participants gave consent directly or through a surrogate when appropriate.

Index Evaluation of Subjects Data were collected through interviews by trained research assistants, and physical and neurologic examinations were conducted by study neurologists. When possible, data were obtained directly from subjects using standardized data collection instruments. When the subject was unable to provide answers, a proxy knowledgeable about the subject’s history was interviewed. Assessments were conducted in English or Spanish, depending on the primary language of the participant. Race/ethnicity was based on self-identification through a series of interview questions modeled after the U.S. Census and conforming to the standard definitions outlined by Directive 15.31 All participants responding affirmatively to being of Spanish origin or identifying themselves as Hispanic were classified as such. All participants classifying themselves as white without any Hispanic origin, or black without any Hispanic origin were classified as white, non-Hispanic, or black, non-Hispanic, respectively. Standardized questions were adapted from the Behavioral Risk Factor Surveillance System32 by the Centers for Disease Control and Prevention regarding the following conditions: hypertension, diabetes, hypercholesterolemia, peripheral vascular disease, transient ischemic attack, cigarette smoking, and cardiac conditions such as myocardial infarction, coronary artery disease, angina, congestive heart failure, atrial fibrillation, other arrhythmias, and valvular heart disease. Standard techniques were used to measure blood pressure, height, weight, and fasting glucose as described previously.24,29,30 Fasting lipid panels (including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides)

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were measured using a Hitachi 705 automated spectrometer (Boehringer, Mannheim, Germany). Hypertension was defined as described previously,24,29,30 and diabetes mellitus was defined by a fasting blood glucose level ⱖ127 mg/dL, the subject’s self-report of such a history, or insulin or oral hypoglycemic use. The definitions are noted in the legends. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and was categorized as mild (NIHSS ⬍6), moderate (NIHSS 6 to 13), or severe (NIHSS ⱖ14). This categorization was based on previous analyses of stroke severity in relation to stroke outcome from our population,33 as well as use in a recent clinical trial of a neuroprotective agent.34 Stroke diagnostic evaluation included computed tomography and/or magnetic resonance imaging of the brain, ultrasound evaluation of the extracranial and intracranial cerebral vessels, and transthoracic or transesophageal echocardiogram as appropriate. Assessment of stroke subtype using modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria35 was determined by a consensus of stroke neurologists, using all available information, as described previously.36

Assessment of Leukocyte Counts Leukocyte counts were measured using automated cell counters via standard techniques (Coulter STK-R and STK-S; Coulter Electronics, Hialeah, FL, and Sysmex SE9500; TOA Medical Electronics, Kobe, Japan). Whole blood was collected in 5-mL EDTA anticoagulated tubes by a trained phlebotomist. The automated cell counter aspirated a sample from the collection tube, and after lysis of red blood cells and platelets, leukocytes were counted using a standard direct current detection method. Normal values for leukocytes in the hematology laboratory are 3.54 to 9.06 ⫻ 109/L. Quality control is maintained by the laboratory using standard procedures. The coefficient of variation for repeated measurements on samples from individual hospitalized patients was maintained at ⱕ2.5%.

Follow-Up and Outcome Assessment Follow-up evaluations were conducted at 6 months and then annually for 5 years. The 6-month evaluation was conducted by telephone and consisted of an interview of the patient, family member, or caregiver. Information on vital status, functional status, and intercurrent symptoms, illness, or hospitalization were collected. Annual in-person follow-up was conducted at the medical center and included interviews as at the 6-month followup, as well as measurement of vital signs and a physical and neurologic examination. Patients unable or unwilling to come to the medical center were visited by a member of the research staff, and the evaluation was conducted at home or in an alternative place of residence (eg, nursing

home). An ongoing surveillance system of admissions to the CUMC and other local hospitals, described previously,37 was also used to identify study participants who experienced recurrent stroke, MI, hospitalization, or death. When available, medical records were reviewed for all outcome events including death. All outcome events were reviewed by a specially trained research assistant. MI was validated by review by a study cardiologist, and strokes by a study neurologist. Deaths were also validated by a study physician.

Statistical Analyses Statistical analyses were conducted using SAS software (Version 8.2; SAS Institute, Cary, NC). For descriptive purposes, means were calculated for continuous variables and proportions for categorical variables among the cohort of stroke patients. Cox proportional hazard models were constructed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of leukocyte count on outcome after adjusting for other potential risk factors. Further analyses were conducted for each of the individual outcome events (recurrent stroke, MI, and death), and also after limiting the analysis to patients who survived 30 days.

Results Description of the Study Population The mean age of the 655 incident ischemic stroke patients was 69.7 ⫾ 12.7 years. Forty-five percent (44.6%; n ⫽ 292) were men; 51.3% (n ⫽ 336) of the patients were Hispanic, 18.9% (n ⫽ 124) were white non-Hispanic, 27.6% (n ⫽ 181) were black non-Hispanic, and 2.1% (n ⫽ 14) were other race/ethnicity. White non-Hispanics (n ⫽ 124; mean age, 77.2 ⫾ 12.1 years) were older than black non-Hispanics (n ⫽ 181; mean age, 70.3 ⫾ 11.5 years) and Hispanics (n ⫽ 336; mean age, 66.6 ⫾ 12.3 years). The distribution of sociodemographic factors, comorbid vascular diseases, and conventional atherosclerotic risk factors is shown in Table 1. Blood samples were drawn at the time of admission. These were performed at ⱕ24 hours after stroke onset in 70.4% of patients, ⱕ48 hours in 81.0% of patients, and ⱕ72 hours in 85.9% of patients. The mean leukocyte count for the entire cohort was 9.1 ⫾ 4.7 ⫻ 109/L (median, 8.0; interquartile range, 6.5 to 10.4). The mean leukocyte count in a simultaneously acquired stroke-free cohort of similar age (mean age, 68.6 years) was 6.29 ⫾ 2.01 ⫻ 109/L.24 The leukocyte count was greater for those with more severe strokes, and leukocyte count at the time of stroke differed slightly by race/ethnicity (Table 2). The mean leukocyte count was 10.3 ⫾ 4.8 among white nonHispanics, 9.0 ⫾ 3.6 among Hispanics, and 8.3 ⫾ 6.3 among black non-Hispanics. There was no difference by age or sex (Table 2).

LEUKOCYTE COUNT AND STROKE PROGNOSIS

Table 1. Characteristics of participants

Completed high school Hypertension Diabetes mellitus Cardiac disease Current smoking Ever smoked Total cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL)

n

Prevalence (%) or mean ⫾ SD

213 463 213 282 129 349 575 520 520

33.1 70.7 32.6 43.1 19.8 53.5 193.5 ⫾ 45.5 40.1 ⫾ 12.3 121.7 ⫾ 40.1

Hypertension was defined as a systolic blood pressure recording ⱖ 160 mm Hg or a diastolic blood pressure recording ⱖ 95 mm Hg or the patient’s self-report of a history of hypertension or antihypertensive use. Diabetes mellitus was defined by a fasting blood glucose level ⬎126 mg/dL, the patient’s self-report of such a history, or insulin or hypoglycemic use. Not all data were available for all participants. Abbreviations: SD, standard deviation; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Short-Term Outcomes The rate of combined recurrent stroke, MI, or death at 30 days was 7.3%. Early outcomes included 12 recurrent strokes and 36 deaths. In an unadjusted model, leukocyte count was a significant independent predictor of 30-day risk of recurrent stroke, MI, or death (HR per unit increase in leukocytes, 1.05; 95% CI, 1.03 to 1.07) (Table 3). After adjusting for age, sex, race/ethnicity, hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, congestive heart failure and stroke severity, leukocyte count remained a significant predictor of recurrent stroke, MI, or death (HR per unit increase in leukocytes, 1.07; 95% CI, 1.00 to 1.13) (Table 3). Severe stroke (NIH Stroke Scale score ⱖ 14) was also a significant independent predictor of outcome at 30 days in the multivariate model (HR, 7.60; 95% CI, 3.45 to 16.81). The effect of leukocyte count was stronger for 30-day mortality (adjusted HR per unit increase in leukocytes, 1.10; 95% CI, 1.03 to 1.17) (Table 3). Recurrent stroke and MI occurred less commonly, and no significant association was found for leukocyte count with these outcomes assessed in combination or independently.

Long-Term Outcomes The outcome event rate at 5 years was 48% with 86 recurrent strokes, 15 MIs, and 214 deaths. Leukocyte count was a significant independent predictor of combined events (HR per unit increase in leukocytes, 1.04; 95% CI, 1.02 to 1.06) (Table 4). After adjusting for age, sex, race/ethnicity, other risk factors, and stroke severity, leukocyte count remained a significant predictor of 5-year outcome (adjusted HR per unit increase in leukocytes, 1.04; 95% CI, 1.00 to 1.07) (Table 4). Age over 70,

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atrial fibrillation, hypertension, and severe stroke were also significant independent predictors of outcome in the multivariate model. Death was the most common outcome event, accounting for 68% of events. In analyses restricted to mortality alone, over 5 years there was a significant association of leukocyte count with death (unadjusted hazard ratio per unit increase leukocytes, 1.05; 95% CI, 1.03 to 1.07) (Table 4). This effect remained after adjustment for demographics, medical risk factors, and stroke severity (HR per unit increase in leukocytes, 1.05; 95% CI, 1.01 to 1.09) (Table 4). Analyses were also conducted by leukocyte count quartile. Quartiles of leukocyte counts were defined as ⬍6.5, 6.5 to ⬍8.0, ⱖ8.0 to ⬍10.4, and ⱖ10.4 ⫻ 109/L. There was a significant association for both the combined outcome of recurrent stroke, MI, or death and for death alone in both the third and fourth quartiles compared with the first quartile, after adjustment for demographic and medical risk factors. The adjusted HR for recurrent stroke, MI, or death was the same for those in the third and fourth quartiles of leukocyte count: 1.51 (95% CI, 1.05 to 2.16) and 1.49 (95% CI, 1.03 to 2.16), respectively. The effect was stronger for death alone as outcome: adjusted HRs of 1.80 (95% CI, 1.18 to 2.74) and 1.98 (95% CI, 1.29 to 3.03) for quartiles 3 and 4, respectively. After additional adjustment for stroke severity, however, the effect was attenuated. There was no longer a significant association of leukocyte count and combined outcome events

Table 2. Mean leukocyte counts among different subgroups of patients

Patient group

n

Leukocyte count (Mean ⫾ SD [⫻ 109/L])

Overall Men Women Non-Hispanic whites Non-Hispanic blacks Hispanics Age ⬍70 years Age ⬎70 years Stroke severity NIH SS 0–5 NIH SS 6–14 NIH SS ⱖ14 Stroke subtype Lacunar Large-vessel atherosclerotic Cardioembolism Cryptogenic Other

631 277 354 123

9.1 ⫾ 4.7 9.0 ⫾ 4.2 9.1 ⫾ 5.1 10.3 ⫾ 4.8

168

8.3 ⫾ 6.3

327 303 328

9.0 ⫾ 3.6 8.9 ⫾ 4.2 9.2 ⫾ 5.2

283 247 101

8.3 ⫾ 3.2 9.2 ⫾ 5.8 10.8 ⫾ 4.9

143 98

8.0 ⫾ 3.3 9.4 ⫾ 3.9

123 242 20

9.9 ⫾ 4.5 9.0 ⫾ 5.8 9.7 ⫾ 4.0

Abbreviations: SD, standard deviation. NIH SS, National Institutes of Health stroke scale.

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Table 3. Leukocyte count as predictor of 30-day outcome after first ischemic stroke Recurrent stroke, MI, or death

Unadjusted Adjusted for demographics* Adjusted for demographics and medical risk factors† Adjusted for demographics, medical risk factors, and stroke severity‡

Death

Hazard ratio per unit increase in leukocyte count

95% confidence interval

Hazard ratio per unit increase in leukocyte count

95% confidence interval

1.05 1.05 1.04

1.03–1.07 1.03–1.07 1.02–1.07

1.06 1.06 1.06

1.04–1.08 1.04–1.08 1.03–1.08

1.07

1.00–1.13

1.10

1.03–1.17

*Adjusted for age, sex, and race-ethnicity. †Adjusted for age, sex, race-ethnicity, hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, and congestive heart failure. ‡Adjusted for age, sex, race-ethnicity, hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, congestive heart failure, and stroke severity (NIH stroke scale 0 –5, 6 –14, or ⱖ14).

(adjusted HRs 1.28 [95% CI, .89 to 1.84] and 1.17 [95% CI, .80 to 1.70], respectively, for the third and fourth quartiles of leukocyte count. For mortality alone, the severityadjusted HRs were 1.42 (95% CI, .93 to 2.18) and 1.40 (95% CI, .90 to 2.18) for quartiles 3 and 4, respectively.

Outcomes Among 30-Day Stroke Survivors When analyses of combined outcome events were restricted to 30-day survivors of stroke, leukocyte count was no longer a significant predictor of long-term risk of stroke, MI, or death (adjusted HR per unit increase in leukocytes, 1.01; 95% CI, .97 to 1.05). Leukocyte count also failed to predict death alone among 30-day survivors (adjusted HR, 1.02; 95% CI, .97 to 1.06). Analyses of outcome were further stratified by stroke severity among 30-day survivors. Among those with moderate strokes

(NIH stroke scale 6 to 13; n ⫽ 189), leukocyte count was strongly and significantly associated with risk of stroke, MI, or death (adjusted HR, 1.14; 95% CI, 1.06 to 1.23). Among those with severe strokes (NIH stroke scale ⱖ14; n ⫽ 101), there was a trend toward an increased risk of an adverse outcome, but the numbers were smaller, limiting statistical power (adjusted HR, 1.04; 95% CI, .99 to 1.10). In those with mild strokes (NIH stroke scale 0 to 5; n ⫽ 308), leukocyte count did not increase the risk of stroke, MI, or death (adjusted HR, .96; 95% CI, .89 to 1.04).

Discussion We found that an elevation in leukocyte count measured shortly after the onset of an ischemic stroke is predictive of prognosis after stroke. The effect on mortal-

Table 4. Leukocyte count as a predictor of long-term risk after first ischemic stroke Recurrent stroke, MI, or death

Unadjusted Adjusted for demographics* Adjusted for demographics and medical risk factors† Adjusted for demographics, medical risk factors, and stroke severity‡

Death

Hazard ratio per unit increase in leukocyte count

95% confidence interval

Hazard ratio per unit increase in leukocyte count

95% confidence interval

1.04 1.04 1.04

1.02–1.06 1.02–1.06 1.02–1.06

1.05 1.05 1.05

1.03–1.07 1.03–1.07 1.03–1.07

1.04

1.00–1.07

1.05

1.01–1.09

*Adjusted for age, sex, and race-ethnicity. †Adjusted for age, sex, race-ethnicity, hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, and congestive heart failure. ‡Adjusted for age, sex, race-ethnicity, hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, congestive heart failure, and stroke severity (NIH stroke scale 0 –5, 6 –14, or ⱖ14).

LEUKOCYTE COUNT AND STROKE PROGNOSIS

ity was most marked, and it was primarily associated with short-term (ie, 30-day) prognosis. The magnitude of this increase in risk of death was approximately 5% for every unit increase in white blood cell count. In clinical terms, compared with a patient with a white cell count of 5.0 ⫻ 109/L at 24 hours after stroke, a patient with a leukocyte count of 10 ⫻ 109/L at 24 hours after stroke would have an approximately 25% greater likelihood of dying after accounting for other risk factors and stroke severity. There are several reasons why an elevated leukocyte count could be associated with an increased risk of future death, MI, or recurrent stroke after a first stroke. Because the effect of leukocyte count was present at 30 days, but less apparent among 30-day survivors of stroke, it is possible that the increased risk associated with an elevated leukocyte count is strongest in the short term. Leukocyte count may thus reflect the increased risk of mortality due to early infection after stroke. Pneumonia, urinary tract infections, and other infections occur commonly after stroke.23 Fever has also been shown to be a poor prognostic indicator after stroke.38 We do not have detailed data on the infections or febrile status complicating the acute strokes of the patients in our study to address this issue more directly, however. Elevated leukocyte count could also be a reflection of the severity of the patient’s stroke. Stroke severity is a well-recognized indicator of prognosis after stroke.33,39 Leukocyte count was elevated among those with more severe strokes. The effect of elevated leukocyte count on mortality persisted after adjusting for stroke severity, however, suggesting an independent effect on prognosis as well. In addition, in analyses stratified by the severity of stroke, we found that the effect of leukocyte count was most pronounced among those with strokes of moderate severity, suggesting that the increased risk of an adverse prognosis associated with an elevated leukocyte count is not limited to those with severe strokes, who are at highest risk of infection. Alternatively, leukocyte count could be a marker of an increased inflammatory state predisposing the patient toward a recurrent vascular event. Prospective studies of vascular disease risk factors in subjects free of disease at baseline have found an association between leukocyte count and risk of first episode of atherosclerotic heart disease1-6 and stroke.19-21 Other studies have found that elevated levels of inflammatory markers predict prognosis after cardiac events. Elevated levels of IL-1 receptor antagonist,15 IL-6,13 IL-8,16 and tumor necrosis factor (TNF)-␣17 at the time of hospitalization predict a worse prognosis in patients with MI and unstable angina. Highsensitivity C-reactive protein (hsCRP) in particular has been associated with mortality after unstable angina,40 MI,41 and in those with stable angiographic evidence of disease.42 Limited data are available on the relationship of inflammatory markers to outcome after stroke, however,

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and no population-based studies have assessed the significance of leukocyte count at the time of stroke as a predictor of future outcome. In a post hoc analysis of a large clinical trial of secondary prevention of ischemic events,22 those in the third and fourth quartiles of leukocyte count at baseline were at increased risk of ischemic stroke, MI, and vascular death. The risk ratio for those in the highest quartile (risk ratio, 1.42) was comparable to the increased risk found in our acute stroke patients in the highest quartile (HR, 1.49). Our results confirm these results and also extend these findings to a populationbased sample of acute stroke patients. Other studies have examined cytokine levels and other markers after stroke as prognostic indicators. Vila et al43 found that IL-6, but not TNF-␣, measured at baseline was an independent predictor of worsening in the first 24 hours after stroke. Beamer et al44 found similar results with IL-6 and IL-1 receptor antagonist. Muir et al45 found that hsCRP levels above 10.1 when measured within 72 hours of stroke predicted increased mortality over a follow-up period of up to 4 years. Arenillas et al46 measured hsCRP levels at least 3 months after a first ischemic stroke or TIA and found that those in the highest quintile of CRP had significantly increased risk of subsequent stroke or MI. DiNapoli et al47 similarly found that an hsCRP level ⱖ15 mg/L at discharge was significantly associated with occurrence of a new vascular event or death at 1 year. Winbeck et al48 found that the measurement of CRP at 24 or 48 hours, but not at admission, also predicted outcome. These studies were limited, however, in having few relatively small numbers of subjects, being hospital-based, and utilizing post hoc cutoffs for marker levels. Further study is needed to determine the clinical value of leukocyte count and other inflammatory markers in post-stroke risk stratification. Most of the events occurring in our stroke patient population were fatal events. The strongest effect of leukocyte count on outcome thus appeared to be on overall mortality. Nonfatal recurrent stroke and myocardial infarction occurred less often, however, making it difficult to draw conclusions about the relationship of leukocyte count to nonfatal vascular events. Our study has several limitations. We collected no systematic information on infections or other complications, such as deep venous thrombosis, which might increase leukocyte count occurring at the time of stroke. It also would have been helpful to have data on leukocyte count differentials of the subjects. Other studies have found neutrophil levels to be most predictive of future events.22 Other evidence suggests that circulating levels of specific white cell types, such as the CD4⫹CD28null subset of T lymphocytes, may be associated with unstable angina.49 It remains unsettled whether circulating levels of specific leukocyte types are associated with subclinical atherosclerosis or stroke. In summary, our data support an association between leukocyte count and prognosis after stroke. Early and

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aggressive treatment of infectious complications after stroke may thus improve prognosis. Some clinical trials in patients with coronary artery disease,50-52 as well as animal studies,53 have provided pilot evidence indicating that the risk of atherosclerotic disease associated with infections may be modifiable. Evidence from other studies suggests that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, may reduce levels of inflammatory markers associated with vascular disease.54,55 Corroboration from larger prospective studies of the role of inflammatory and infectious markers in stroke might lead to clinical trials with novel anti-inflammatory or anti-infectious therapies to retard atherosclerosis or prevent incident and recurrent stroke.

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