The white blood cell (WBC) count is marker of systemic inflammation. It is determined routinely by means of well-standardized automated methods at low cost and with high precision. Consequently, the WBC count is often included in routine clinical checkups. Data from multiple observational studies have demonstrated that WBC count has an independent ability to predict all-cause mortality [
The aim of the present study was to determine the prognostic impact of WBC count on all-cause, cardiovascular, and noncardiovascular mortality during an 11-year followup in a general population of 75-year-olds.
The city of Västerås (130,000 inhabitants) situated in central Sweden has a population that is socioeconomically representative for the country. In 1997 a random sample of 618 of the 1,100 inhabitants born in 1922 (i.e., 75 year old) were invited to participate in a cardiovascular health survey. Four hundred thirty-two individuals (210 men and 222 women) finally accepted the invitation, corresponding to a participation rate of 70%. Reasons for nonparticipation were: Unknown (
The study was approved by the research ethics committee of Uppsala University, Sweden, and was conducted in accordance with the Declaration of Helsinki. All subjects gave their informed consent.
The blood samples were collected in a fasting state in the morning. WBCs were counted with an automated blood cell counter, Cell-Dyn 3500 (Abbott). Serum triglycerides, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were determined enzymatically on an automated analyser system (Hitachi 717, Boehringer Mannheim). Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula [
Blood pressure (BP) was measured to the nearest five mm Hg with a mercury sphygmomanometer with the subjects in a supine position having rested for five minutes.
All-cause mortality served as the primary end point. By means of the Swedish population register, the study cohort was followed for all-cause mortality from the index examination in 1997 until November 1, 2008. Only one individual (a man) was lost to followup (reason: migration). Causes of death until November 1, 2008, were obtained from the Swedish Cause of Death Register. The 10th revision of the International Statistical Classification of Diseases (ICD) was used to identify causes of death. For the present analyses, causes of death were grouped into two categories: cardiovascular, ICD 10, I00-I99, or noncardiovascular comprising all other causes of death. The study was not powered for analyzing more detailed categories of death causes.
Continuous variables were summarized by medians and interquartile ranges and categorical variables by numbers and proportions. The Wilcoxon-Mann-Whitney rank sum test was used to compare continuous variables and Fisher’s exact test to compare categorical variables.
Crude and adjusted prospective associations of the WBC count with mortality were assessed by hazard ratios (HR) and corresponding 95% confidence intervals (CI) using uni- and multivariable Cox proportional hazard regression. For continuous variables, the assumption of proportional hazards (PH) was assessed by examining the variables’ interaction with time or a function of time (e.g., log(time)) in a Cox model. The PH assumption for categorical variables was assessed by visual inspection of the log (−log(cumulative survival)). Cumulative survival was estimated by means of the Kaplan-Meier survival curves. Associations between continuous variables were assessed by Spearman’s rank correlation. The sex disparity in the strength of the association between WBC count and other markers was assessed by including the interaction term between sex and WBC count in a regression model with the marker as dependent variable.
A two-sided
The distribution of the WBC counts among the participants at baseline was positively skewed. The ranges of the WBC counts (in 109/L) were 3.0–12.0 for men and 2.9–10.6 for women. The median (interquartile range) was 6.3 (5.4–7.2) for men and 5.7 (4.9–6.8) for women. The mean (SD) was 6.36 (1.44) for men and 5.90 (1.46) for women. The sex disparity was statistically significant (
Table
Sex-specific baseline characteristics of the study cohort according to survival status. Categorical variables are shown as number (%) and continuous variables as median (interquartile range).
Survivors | Nonsurvivors | |||
---|---|---|---|---|
Men |
Women |
Men |
Women |
|
Current smoker | 9 (9) | 8 (5) | 18 (17) | 8 (12) |
Known hypertension | 14 (14)† | 39 (25) | 41 (38)† | 26 (39) |
Known diabetes | 6 (6) | 9 (6) | 9 (8) | 8 (12) |
Prior myocardial infarction | 9 (9)† | 4 (3) | 22 (20)† | 6 (9) |
Statin medication | 1 (1) | 4 (3) | 6 (6) | 3 (4) |
WBC count (109/L) | 6.1 (5.4–6.8)† | 5.6 (4.7–6.7)‡ | 6.4 (5.5–7.4)† | 5.8 (5.1–7.1)‡ |
BMI (kg/m2) | 25.4 (23.1–26.8) | 26.2 (23.7–29.3) | 25.1 (23.7–27.3) | 25.8 (23.4–28.3) |
Plasma glucose (mmol/L) | 5.8 (5.4–6.4) | 5.9 (5.4–6.4)‡ | 5.9 (5.4–6.6) | 6.0 (5.5–7.2)‡ |
Systolic BP (mmHg) | 160 (144–180) | 165 (150–190) | 160 (150–180) | 165 (150–180) |
Diastolic BP (mmHg) | 83 (75–90) | 85 (80–90) | 85 (80–91) | 85 (75–90) |
Total cholesterol (mmol/L) | 6.0 (5.4–6.8) | 6.6 (5.8–7.3) | 5.9 (5.3–6.5) | 6.5 (5.9–7.0) |
LDL-cholesterol (mmol/L) | 3.8 (3.2–4.7) | 4.1 (3.4–4.8) | 3.8 (2.9–4.3) | 4.2 (3.6–4.8) |
HDL-cholesterol (mmol/L) | 1.4 (1.2–1.7)† | 1.6 (1.4–2.0) | 1.4 (1.2–1.5)† | 1.5 (1.2–1.9) |
Triglycerides (mmol/L) | 1.4 (1.0–1.8) | 1.4 (1.1–2.1) | 1.6 (1.1–2.0) | 1.5 (1.1–2.0) |
There were strong correlations between WBC count and plasma glucose and HDL-C, respectively, in women (Spearman correlation 0.29;
During a median followup of 11.4 years (range 0.2–11.8 years) 108 (52%) men and 67 (30%) women died. The total number of person-years with followup was 4088 implying 4.3 deaths per 100 person-years at risk (men 5.9; women 3.0). In men there were 48 deaths from cardiovascular causes and 60 from noncardiovascular causes (including 31 attributed to malignancy). The corresponding figures for women were 32 deaths from cardiovascular causes and 35 from noncardiovascular causes (including 13 attributed to malignancy). The cause of death was unknown in one man and three women.
The mortality among the 30% of invited individuals who did not participate in the investigation was considerably higher (67%) than among the participants.
Table
Cox regression analyses of all-cause, cardiovascular, and noncardiovascular mortality according to WBC count stratified by sex (
HR | 95% CI |
|
|
---|---|---|---|
Men | |||
All-cause mortality | |||
Model 1 | 1.16 | 1.03–1.32 | 0.016 |
Model 3 | 1.12 | 0.98–1.28 | 0.092 |
Cardiovascular mortality | |||
Model 1 | 1.21 | 1.01–1.45 | 0.038 |
Model 2 | 1.13 | 0.95–1.35 | 0.181 |
Noncardiovascular mortality | |||
Model 1 | 1.12 | 0.95–1.33 | 0.171 |
Model 2 | 1.09 | 0.92–1.30 | 0.331 |
Women | |||
All-cause mortality | |||
Model 1 | 1.28 | 1.10–1.50 | 0.002 |
Model 3 | 1.23 | 1.03–1.47 | 0.020 |
Cardiovascular mortality | |||
Model 1 | 1.30 | 1.04–1.62 | 0.021 |
Model 2 | 1.21 | 0.96–1.53 | 0.110 |
Noncardiovascular mortality | |||
Model 1 | 1.27 | 1.03–1.58 | 0.028 |
Model 2 | 1.20 | 0.95–1.52 | 0.119 |
All hazard ratios (HR) are per 109/L increase in WBC count. Model 1: crude HR, model 2: HR adjusted for current smoking and known hypertension, and model 3: HR adjusted for current smoking, known hypertension, prior myocardial infarction, known diabetes, total cholesterol, HDL-cholesterol, and BMI.
In an additional analysis we excluded deaths within 5 years, thereby reasonably excluding prevalent severe disease at the time of inclusion in the study. For all-cause mortality, the HR (95%CI) was 1.11 (0.96–1.29;
Figure
Kaplan-Meier curves showing cumulative all-cause mortality according to sex-specific WBC count tertiles.
The principal finding in the present community-based study of 75-year-olds is a considerable long-term prognostic significance of the basic WBC count, especially among women. Determination of the WBC count is a well standardized and cost-effective procedure with excellent precision and it is often included in routine checkups. Thus, the present finding is of potential clinical importance. We previously reported the poor prognostic value of serum cholesterol in the present population [
The restriction of the present investigation to one age class made it possible to leave age out of account as covariate, thereby enabling us to draw conclusions about WBC counts and mortality despite a relatively low number of participants in the study. This advantage, of course, was obtained at the cost of generalizing our conclusions to people not 75 years of age and to people living in other geographical areas. However, our conclusions seem reasonably applicable to north Europeans and white North Americans in their seventies. The strength of the present study is increased by a relatively long time of followup.
The examined communitybased cohort was well defined and the participation rate was rather high. Reasons for nonparticipation were accounted for and included a substantial fraction of individuals already under medical attention. This is a likely explanation for the higher mortality among nonparticipants than among participants. Similar studies from other centers need to confirm the results from the present study.
It is well known that the WBC count is higher among men than among women [
Multiple observational studies have demonstrated that WBC counts have substantial ability to predict all-cause mortality [
The sex difference in WBC count found in the present study corresponds to that found in people over 75 years of age in the United States National Health and Nutrition Examination Survey (NHANES) [
Each age class represents survivors from younger age classes. Consequently, clinically established risk factors among middle-aged people may not be applicable to elderly people, whereas other factors, exemplified by the WBC count, may assume greater importance. Our finding of this test’s relatively strong prognostic ability among the elderly is clinically important.
Concerning the prognostic aspect of the WBC count, two past studies have included elderly women. In a 10-year followup of 705 men and women, more than 85 years old, in Leiden in The Netherlands, Willems et al. [
Concerning elderly men, Weijenberg et al. [
The WBC count tends to cluster with other established risk factors such as tobacco smoking [
The pathophysiological mechanisms that link elevated WBC count to increased mortality are not well understood. Thus, it is not known whether elevated WBC count is involved directly in the pathogenesis of vascular diseases or is merely a risk indicator of other factors causing vascular damage [
By means of our data, the mortality risk among elderly people at different levels of basal WBC counts (Figure
Of note, this prognostic ability contrasts with the serum cholesterol’s lack of ability to predict all-cause mortality among the elderly [
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are grateful to Marja-Leena Ojutkangas for her excellent care of the study participants and data management. The authors are also grateful to Mattias Rehn for excellent technical support. This work was supported by Västmanland County Council Research foundation.