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1.  Comparative Value of Simple Inflammatory Markers in the Prediction of Left Ventricular Systolic Dysfunction in Postacute Coronary Syndrome Patients 
Mediators of Inflammation  2009;2009:826297.
Objectives. We sought to assess the comparative value of inflammatory markers on the occurrence of left ventricular systolic dysfunction (LVSD) after an acute coronary syndrome (ACS). Methods. During 2006–2008, 760 patients with an ACS were enrolled. C-reactive protein (CRP) and white blood cell (WBC) count were measured during the first 12 hours of hospital admission. Results. CRP levels and WBC count were significantly higher in those who developed LVSD compared to those who did not. The analysis revealed that a 10 mg/dL increase of CRP levels and a 1000/μL increase in WBC are associated with a 6% and a 7% increase in the likelihood of developing LVSD, respectively. Furthermore, WBC count at entry and CRP have almost the same predictive value for development of LVSD after an ACS (R2 = 0.109 versus R2 = 0.093). Conclusions. Serum CRP levels and WBC count at entry are almost equally powerful independent predictors of LVSD, after an ACS.
PMCID: PMC2686251  PMID: 19503842
2.  Combining white blood cell count and thrombosis for predicting in-hospital outcomes after acute myocardial infraction 
Admission white blood cell (WBC) count and thrombosis in myocardial infarction (TIMI) risk score have been associated with adverse outcomes after acute myocardial infarction (AMI). This study investigated the joint effect of WBC count and TIMI risk score on predicting in-hospital outcomes in patients with AMI.
Materials and Methods:
WBC count and TIMI risk score were measured at the time of hospital admission in 70 patients with AMI. Echocardiogram was done on prior to discharge by a cardiologist and ejection fraction (EF) was determined according to the Simpson formula. Patients were stratified into tertiles (low and high) based on WBC count and TIMI risk score.
Patients with a high WBC count had a 5.0-fold increase in-hospital congestive heart failure and 2.2 increases in mortality compared with those with a low WBC count. Patients with a high TIMI risk score had a 10-fold increase in congestive heart failure presentation and mortality compared with those with a low TIMI risk score. When a combination of different strata for each variable was analyzed, a stepwise increase in mortality was seen. There were a few number of patients with a high WBC count and low TIMI risk score or with a low WBC count and high TIMI risk score. These patients had an intermediate risk, whereas those with a high WBC count and TIMI risk score had the highest risk.
These findings suggested that a simple combination of WBC count and TIMI risk score might provide further information for predicting outcomes in patients with AMI.
PMCID: PMC3162703  PMID: 21887024
Heart failure; infarction; ST elevation myocardial; white blood cell
3.  Effect of Different Doses of Aerobic Exercise on Total White Blood Cell (WBC) and WBC Subfraction Number in Postmenopausal Women: Results from DREW 
PLoS ONE  2012;7(2):e31319.
Elevated total white blood cell (WBC) count is associated with an increased risk of coronary heart disease and death. Aerobic exercise is associated with lower total WBC, neutrophil, and monocyte counts. However, no studies have evaluated the effect of the amount of aerobic exercise (dose) on total WBC and WBC subfraction counts.
To examine the effects of 3 different doses of aerobic exercise on changes in total WBC and WBC subfraction counts and independent effects of changes in fitness, adiposity, markers of inflammation (IL-6, TNF-α, C-reactive protein), fasting glucose metabolism, and adiponectin.
Data from 390 sedentary, overweight/obese postmenopausal women from the DREW study were used in these analyses. Women were randomized to a non-exercise control group or one of 3 exercise groups: energy expenditure of 4, 8, or 12 kcal kg−1⋅week−1 (KKW) for 6 months at an intensity of 50% VO2peak.
A dose-dependent decrease in total WBC counts (trend P = 0.002) was observed with a significant decrease in the 12KKW group (−163.1±140.0 cells/µL; mean±95%CI) compared with the control (138.6±144.7 cells/µL). A similar response was seen in the neutrophil subfraction (trend P = 0.001) with a significant decrease in the 12KKW group (−152.6±115.1 cells/µL) compared with both the control and 4KKW groups (96.4±119.0 and 21.9±95.3 cells/µL, respectively) and in the 8KKW group (−102.4±125.0 cells/µL) compared with the control. When divided into high/low baseline WBC categories (median split), a dose-dependent decrease in both total WBCs (P = 0.003) and neutrophils (P<0.001) was observed in women with high baseline WBC counts. The effects of exercise dose on total WBC and neutrophil counts persisted after accounting for significant independent effects of change in waist circumference and IL-6.
Aerobic exercise training reduces total WBC and neutrophil counts, in a dose-dependent manner, in overweight/obese postmenopausal women and is especially beneficial for those with systemic low grade inflammation.
Clinical Trials Identifier: NCT00011193
PMCID: PMC3281960  PMID: 22363616
4.  Frailty, Inflammation, and Immunity 
Aging and Disease  2011;2(6):466-473.
Frailty is an important geriatric syndrome that is characterized by multisystem dysregulation, leading to decreased physiological reserve and increased vulnerability for adverse health outcomes. A large number of studies have shown a heightened inflammatory state marked by elevated levels of inflammatory molecules, such as IL-6 and C-reactive protein (CRP), and increased counts of white blood cell (WBC) and WBC subpopulations in frail older adults. It has been postulated that this heightened inflammatory state, or chronic inflammation, may play an important role in the pathogenesis of frailty, directly or through its detrimental influence to other physiologic systems. Inflammatory and immune activation mediated by monocytes and macrophages demonstrated by upregulated expression of specific stress responsive inflammatory pathway genes and elevated neopterin levels may contribute, at least in part, to this chronically heightened inflammatory state in frailty. Decrease in lipopolysaccharide (LPS)-induced proliferation of the peripheral blood mononuclear cells (PBMCs), one of the functional readouts of the innate immune system, has also been observed in frail older adults. In the adaptive immune system, significant frailty-associated alterations have been identified in the T-cell compartment including expansion of CD8+ and CCR5+ T cells and loss of CD28 expression, above and beyond age-related senescent remodeling. Moreover, frailty is associated with impaired antibody responses to pneumococcal and influenza immunization and poor clinical protection against influenza infection in community-dwelling older adults. Taken together, these findings demonstrate significant inflammatory and immune dysregulation in frail older adults and highlight the need for strategies to improve the immune function for this vulnerable elderly population.
PMCID: PMC3295062  PMID: 22396895
Frailty; inflammation; IL-6; neopterin; influenza immunization
5.  Acute appendicitis: relationships between CT-determined severities and serum white blood cell counts and C-reactive protein levels 
The British Journal of Radiology  2011;84(1008):1115-1120.
The aim of this study was to evaluate the relationships between the severity of appendicitis as depicted on CT and blood inflammatory markers of serum white blood cell (WBC) count and C-reactive protein (CRP).
CT images in 128 patients (109 surgically proven and 19 with clinically excluded appendicitis) were retrospectively reviewed. Two radiologists by consensus evaluated and scored (using a 0, 1 or 2 point scale) severities based on CT-determined appendiceal diameters, appendiceal wall changes, caecal changes, periappendiceal inflammatory stranding and phlegmon or abscess formation. We investigated whether CT findings were significantly related to elevated WBC counts or CRP levels and performed the correlations of WBC counts and CRP levels with CT severity scores. Patients were also subjectively classified using four grades from normal (Grade I) to perforated appendicitis (Grade IV) on the basis of CT findings to evaluate differences in WBC counts and CRP levels between grades.
Only appendiceal wall changes and the phlegmon or abscess formation were related to elevated WBC counts and CRP levels, respectively (p<0.05). CT severity scores were found to be more strongly correlated with CRP levels (r = 0.669) than with WBC counts (r = 0.222). On the basis of CT grades, the WBC counts in Grade I were significantly lower than in other grades (p<0.001), whereas CRP levels in Grade IV were significantly higher than in other grades (p<0.001).
CRP levels were found to correlate with CT-determined acute appendicitis severity and could be a useful predictor for perforated appendicitis, whereas WBC counts might be useful to detect early acute appendicitis.
PMCID: PMC3473821  PMID: 21123307
6.  Systemic inflammatory mediators in post-traumatic Complex Regional Pain Syndrome (CRPS I) - longitudinal investigations and differences to control groups 
The Complex Regional Pain Syndrome I (CRPS I) is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet.
To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP), White Blood Cell Count (WBC), Interleukins 4, 6, 8, 10, 11, 12 (p70), Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-α) and its soluble Receptors I/II, soluble Selectins (E, L, P), Substance-P (SP), and Calcitonin Gene-Related Peptide (CGRP) at different time points in venous blood from patients with acute (AC) and chronic (CC) CRPS I, patients with forearm fractures (FR), with neuralgia (NE), and from healthy volunteers (C).
No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007), FR/C (CGRP p = 0.048) and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049). High interindividual variations were observed. No intra-or interindividual correlation of parameters with clinical course (e.g. chronification) or outcome was detectable.
Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I
PMCID: PMC3352062  PMID: 19380284
CRPS-I; Reflex dystrophy; Inflammation; Cytokines
7.  Diagnostic value of blood inflammatory markers for detection of acute appendicitis in children 
BMC Surgery  2006;6:15.
Acute appendicitis (AA) is a common surgical problem that is associated with an acute-phase reaction. Previous studies have shown that cytokines and acute-phase proteins are activated and may serve as indicators for the severity of appendicitis. The aim of this study was to compare diagnostic value of different serum inflammatory markers in detection of phlegmonous or perforated appendicitis in children.
Data were collected prospectively on 211 consecutive children. Laparotomy was performed for suspected AA for 189 patients. Patients were subdivided into groups: nonsurgical abdominal pain, early appendicitis, phlegmonous or gangrenous appendicitis, perforated appendicitis.
White blood cell count (WBC), serum C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), acid α1-glycoprotein (α1GP), endotoxin, and erythrocyte sedimentation reaction (ESR) were estimated ad the time of admission. The diagnostic performance was analyzed using receiver operating characteristic (ROC) curves.
WBC count, CRP and IL-6 correlated significantly with the severity of appendiceal inflammation. Identification of children with severe appendicitis was supported by IL-6 or CRP but not WBC. Between IL-6 and CRP, there were no significant differences in diagnostic use.
Laboratory results should be considered to be integrated within the clinical assessment. If used critically, CRP and IL-6 equally provide surgeons with complementary information in discerning the necessity for urgent operation.
PMCID: PMC1712352  PMID: 17132173
8.  Diagnostic value of urine sTREM-1 for sepsis and relevant acute kidney injuries: a prospective study 
Critical Care  2011;15(5):R250.
We explored the diagnostic value of a urine soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for early sepsis identification, severity and prognosis assessment, and for secondary acute kidney injury (AKI). We compared this with white blood cell (WBC) counts, serum C-reactive protein (CRP), serum procalcitonin (PCT), urine output, creatinine clearance (CCr), serum creatinine (SCr), and blood urea nitrogen (BUN).
We enrolled 104 subjects admitted to the ICU: 16 cases with systemic inflammatory response syndrome (SIRS); 35 with sepsis and 53 with severe sepsis. Results for urine sTREM-1, WBC, serum CRP and serum PCT were recorded on days 1, 3, 5, 7, 10, and 14. For 17 sepsis cases diagnosed with secondary AKI, comparisons between their urine sTREM-1, urine output, CCr, SCr and BUN at diagnosis and 48 h before diagnosis were made.
On the day of admission to the ICU, and compared with the SIRS group, the sepsis group exhibited higher levels of urine sTREM-1 and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) scores (P < 0.05). Areas under the curve (AUC) shaped by the scores were 0.797 (95% CI 0.711 to 0.884) and 0.722 (95% CI 0.586 to 0.858), respectively. On days 1, 3, 5, 7, 10, and 14, urine sTREM-1, serum PCT and WBC levels registered higher in the severe sepsis group in contrast to the sepsis group (P < 0.05). Urine sTREM-1 and serum PCT levels continuously increased among non-survivors, while WBC and serum CRP levels in both groups declined. For 17 patients with AKI, urine sTREM-1, SCr and BUN levels at 48 h before AKI diagnosis were higher, and CCr level was lower than those for non-AKI subjects (P < 0.05). AUC for urine sTREM-1 was 0.922 (95% CI 0.850 to 0.995), the sensitivity was 0.941, and the specificity was 0.76 (based on a cut-off point of 69.04 pg/ml). Logistic regression analysis showed that urine sTREM-1 and severity were risk factors related to AKI occurrence.
Besides being non-invasive, urine sTREM-1 testing is more sensitive than testing WBC, serum CRP, and serum PCT for the early diagnosis of sepsis, as well as for dynamic assessments of severity and prognosis. It can also provide an early warning of possible secondary AKI in sepsis patients.
Trial Registration identifier NCT01333657
PMCID: PMC3334801  PMID: 22023777
urine; soluble triggering receptor expressed on myeloid cells-1(sTREM-1); sepsis; severity; prognosis; acute kidney injury (AKI); sensitivity; specificity
9.  Relationship between resistin level in serum and acute coronary syndrome or stable angina pectoris*  
Objective: To investigate the relationship between serum resistin level and acute coronary syndrome (ACS) or stable angina pectoris (SAP). Methods: Sixty-five patients, with coronary artery disease, were enrolled and divided into three subgroups: acute myocardial infarction (AMI), unstable angina pectoris (UAP) and SAP, and 26 healthy people were recruited as controls in the cross-sectional study. Serum resistin levels were determined by ELISA (enzyme-linked immunosorbent assay), and WBC (white blood cell count), hsCRP (high sensitive C-reaction protein), CKmax (maximum of creatinkinase), CK-MBmax (maximum of isozyme of creatinkinase) and cTnImax (maximum of troponin) were measured by standard laboratory methods. Results: The serum resistin levels were 4 folds higher in AMI patients, 2.43 folds in UAP patients and 1.12 folds in SAP patients than in the healthy controls (P<0.05). The resistin levels were also significantly different between AMI [(8.16±0.79) ng/ml], UAP [(5.59±0.75) ng/ml] and SAP [(3.45±0.56) ng/ml] groups (P<0.01); WBC, hsCRP, CKmax, CK-MBmax and cTnImax were significantly increased in AMI patients over UAP and SAP patients. Spearman analysis showed that serum resistin levels were positively correlated with WBC (r=0.412, P=0.046), hsCRP (r=0.427, P=0.037), CKmax, CK-MBmax and cTnImax (r=0.731, 0.678, 0.656; P<0.01). Conclusion: Serum resistin levels increased with inflammatory factors and myocardial impairment. The results suggest that human resistin might play an important role in the pathogenesis of atherosclerosis and AMI as an inflammatory factor.
PMCID: PMC2100158  PMID: 18257120
Resistin; Acute coronary syndrome (ACS); Stable angina pectoris (SAP)
10.  Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials 
Heart  2003;89(10):1200-1204.
Background: Raised inflammatory markers are associated with worse outcome after percutaneous coronary interventions (PCI). An increase in the white blood cell (WBC) count is a non-specific response to inflammation. We hypothesised that a raised baseline WBC count would be a predictor of mortality in patients undergoing PCI.
Methods: The association between preprocedural WBC count and long term mortality was studied in 7179 patients enrolled in the EPIC, EPILOG, and EPISTENT trials. The end points were the incidence of myocardial infarction at one year, and one and three year mortality.
Results: There were 188 deaths and 582 myocardial infarctions at one year. While WBC count was a strong predictor of death at one year, with every increase of 1 k/μl (1×106/l) being associated with a hazard ratio (HR) of 1.109 (95% confidence interval (CI) 1.072 to 1.147, p < 0.001), there was no association with myocardial infarction at one year (HR 1.020, 95% CI 0.990 to 1.052, p = 0.195). There were a total of 406 deaths at three years with a strong association between WBC count and three year mortality (HR for every 1 k/μl increase 1.089, 95% CI 1.058 to 1.121, p < 0.001). WBC count remained a significant predictor of mortality after multivariable adjustment (HR for every 1 k/μl increase 1.100, 95% CI 1.069 to 1.131, p < 0.001). The association was significant across multiple subgroups, including diabetes, female sex, clinical presentation, and cigarette smoking.
Conclusion: A raised pre-procedural WBC count in patients undergoing PCI is associated with an increased risk of long term death. These results suggest a key role for inflammation in coronary artery disease.
PMCID: PMC1767915  PMID: 12975419
white blood cell count; percutaneous coronary intervention; inflammation; atherosclerosis
11.  Diabetes, Obesity, and Hypertension May Enhance Associations between Air Pollution and Markers of Systemic Inflammation 
Environmental Health Perspectives  2006;114(7):992-998.
Airborne particulate matter (PM) may lead to increased cardiac risk through an inflammatory pathway. Therefore, we investigated associations between ambient PM and markers of systemic inflammation among repeated measures from 44 senior citizens (≥ 60 years of age) and examined susceptibility by conditions linked to chronic inflammation. Mixed models were used to identify associations between concentrations of fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] averaged over 1–7 days and measures of C-reactive protein (CRP), interleukin-6 (IL-6), and white blood cells (WBCs). Effect modification was investigated for diabetes, obesity, hypertension, and elevated mean inflammatory markers. We found positive associations between longer moving averages of PM2.5 and WBCs across all participants, with a 5.5% [95% confidence interval (CI), 0.10 to 11%] increase per interquartile increase (5.4 μg/m3) of PM2.5 averaged over the previous week. PM2.5 and CRP also exhibited positive associations among all individuals for averages longer than 1 day, with the largest associations for persons with diabetes, obesity, and hypertension. For example, an interquartile increase in the 5-day mean PM2.5 (6.1 μg/m3) was associated with a 14% increase in CRP (95% CI, −5.4 to 37%) for all individuals and an 81% (95% CI, 21 to 172%) increase for persons with diabetes, obesity, and hypertension. Persons with diabetes, obesity, and hypertension also exhibited positive associations between PM2.5 and IL-6. Individuals with elevated mean inflammatory markers exhibited enhanced associations with CRP, IL-6, and WBCs. We found modest positive associations between PM2.5 and indicators of systemic inflammation, with larger associations suggested for individuals with diabetes, obesity, hypertension, and elevated mean inflammatory markers.
PMCID: PMC1513328  PMID: 16835049
air pollution; C-reactive protein; inflammation; metabolic syndrome; particulate matter; susceptibility
12.  Cervical Length and the Risk of Microbial Invasion of the Amniotic Cavity in Women with Preterm Premature Rupture of Membranes 
Journal of Korean Medical Science  2007;22(4):713-717.
The aims of this study were to determine whether sonographically measured cervical length is of value in the identification of microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes (PPROM) and to compare its performance with maternal blood C-reactive protein (CRP), white blood cell count (WBC), and amniotic fluid (AF) WBC. This prospective observational study enrolled 50 singleton pregnancies with PPROM. Transvaginal ultrasound for measurement of cervical length was performed and maternal blood was collected for the determination of CRP and WBC at the time of amniocentesis. AF obtained by amniocentesis was cultured and WBC determined. The prevalence of a positive amniotic fluid culture was 26% (13/50). Patients with positive amniotic fluid cultures had a significantly shorter median cervical length and higher median CRP, WBC, and AF WBC than did those with negative cultures. Multiple logistic regression indicated that only cervical length had a significant relationship with the log odds of a positive AF culture. Transvaginal sonographic measurement of cervical length is valuable in the identification of microbial invasion of amniotic cavity in women with PPROM. Cervical length performs better than AF WBC, maternal blood CRP, and WBC in the identification of a positive amniotic fluid culture.
PMCID: PMC2693825  PMID: 17728515
Cervical Length; Microbial Invasion of the Amniotic Cavity; Preterm Premature Rupture of Membranes
13.  White blood cell count and long term mortality after non-ST elevation acute coronary syndrome treated with very early revascularisation 
Heart  2003;89(4):389-392.
Objective: To evaluate the predictive value of white blood cell count (WBC) for short and long term mortality in patients with non-ST elevation acute coronary syndromes (NSTACS) treated with a very early invasive strategy.
Design: Prospective cohort study in 1391 consecutive patients with NSTACS undergoing very early revascularisation. Patients were stratified according to quartiles of WBC determined on admission.
Results: Kaplan-Meier survival analysis showed a cumulative three year survival of 93.8% in the first quartile of WBC (< 6800/mm3), 94.4% in the second quartile (6800–8000/mm3), 95.1% in the third quartile (8000–10000/mm3), and 82.4% in the fourth quartile (> 10000/mm3) at 36 months (p < 0.001 by log rank). Relative to patients in the three lower WBC quartiles, patients in the highest quartile were three times more likely to die during the hospitalisation (hazard ratio 3.2, 95% confidence interval (CI) 1.5 to 7.1; p = 0.003) and during long term follow up (hazard ratio 3.4, 95% CI 2.2 to 5.3; p < 0.001). By multivariate Cox regression analysis including baseline demographic, clinical, and angiographic covariables, WBC in the highest quartile remained a strong independent predictor of mortality (hazard ratio 3.3, 95% CI 1.9 to 5.6; p < 0.001).
Conclusions: WBC is a strong independent predictor of short and long term mortality after NSTACS treated with very early revascularisation.
PMCID: PMC1769274  PMID: 12639865
white blood cell count; non-ST elevation acute coronary syndromes; revascularisation
14.  Black-White Divergence in the Relation of White Blood Cell Count to Metabolic Syndrome in Preadolescents, Adolescents, and Young Adults: The Bogalusa Heart Study 
Diabetes Care  2010;33(11):2474-2476.
To examine the association between white blood cell (WBC) count and metabolic syndrome (MetS) by growth periods in black versus white individuals in the general population.
The study cohort consisted of 4,184 black and white preadolescents, adolescents, and adults. In this cohort, 743 adults were followed for 8.1–20.8 years longitudinally.
White versus black subjects had a significantly higher WBC count in all age-groups. WBC count was associated with more MetS components in whites than in blacks. Mean values of WBC increased significantly with increasing number of MetS components with adverse levels in adolescents and adults, with a stronger trend in whites. WBC count was longitudinally associated with MetS in whites only (P < 0.001).
The findings on the association between higher WBC count and MetS beginning in childhood, particularly in whites, underscore a potentially mechanistic link between systemic inflammation, MetS, and cardiovascular risk.
PMCID: PMC2963517  PMID: 20798336
15.  Acute phase proteins and white blood cell levels for prediction of infectious complications in status epilepticus 
Critical Care  2011;15(6):R274.
Infections in status epilepticus (SE) patients result in severe morbidity making early diagnosis crucial. As SE may lead to inflammatory reaction, the value of acute phase proteins and white blood cells (WBC) for diagnosis of infections during SE may be important. We examined the reliability of C-reactive protein (CRP), procalcitonin (PCT), and WBC for diagnosis of infections during SE.
All consecutive SE patients treated in the ICU from 2005 to 2009 were included. Clinical and microbiological records, and measurements of CRP and WBC during SE were analyzed. Subgroup analysis was performed for additional PCT measurements in the first 48 hours of SE.
A total of 22.5% of 160 consecutive SE patients had infections during SE. Single levels of CRP and WBC had no association with the presence of infections. Their linear changes over the first three days after SE onset were significantly associated with the presence of infections (P = 0.0012 for CRP, P = 0.0137 for WBC). Levels of PCT were available for 31 patients and did not differ significantly in patients with and without infections. Sensitivity of PCT and CRP was high (94% and 83%) and the negative predictive value of CRP increased over the first three days to 97%. Specificity was low, without improvement for different cut-offs.
Single levels of CRP and WBC are not reliable for diagnosis of infections during SE, while their linear changes over time significantly correlate with the presence of infections. In addition, low levels of CRP and PCT rule out hospital-acquired infections in SE patients.
PMCID: PMC3388641  PMID: 22099124
16.  Procalcitonin and C-Reactive Protein in the Diagnosis and Prediction of Spontaneous Bacterial Peritonitis Associated With Chronic Severe Hepatitis B 
Annals of Laboratory Medicine  2013;33(6):449-454.
Procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) are inflammatory markers used to diagnose severe bacterial infections. We evaluated the diagnostic role of these markers and compared their accuracy for spontaneous bacterial peritonitis (SBP) associated with chronic severe hepatitis B (CSHB).
PCT and CRP concentrations, WBC count, and other hematological parameters were measured in serum from 84 well-characterized patients with CSHB, of whom 42 had SBP. Receiver operating characteristics (ROC) curve analysis was performed to assess the diagnostic accuracy.
PCT and CRP concentrations were significantly higher in the CSHB patients with SBP (n=42) than CSHB patients without SBP (n=42). PCT and CRP concentrations were more accurate than WBC count for the diagnosis of CSHB-associated SBP. The optimal cutoff value of PCT was 0.48 ng/mL. The PCT concentration was significantly correlated with the CRP concentration and WBC count.
Serum PCT and CRP seems to be better markers than WBC for the diagnosis of CSHB patients with SBP.
PMCID: PMC3819445  PMID: 24205495
Chronic severe hepatitis B; Procalcitonin; C-reactive protein; White blood cell
17.  White Blood Cell Count Measured Prior to Cancer Development Is Associated with Future Risk of Venous Thromboembolism – The Tromsø Study 
PLoS ONE  2013;8(9):e73447.
Elevated white blood cell (WBC) count is associated with risk of venous thromboembolism (VTE) in cancer patients initiating chemotherapy. It is not known whether the risk of VTE by WBC count in cancer patients is causal or merely a consequence of the malignant disease. To address this question, we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects who did and did not develop cancer during follow-up in a prospective population-based study.
Baseline characteristics, including WBC and neutrophil counts, were measured in 24304 initially cancer-free subjects who participated in the Tromsø Study in 1994-1995. Incident cancer diagnosis and VTE events were registered up to September 1, 2007. In the cancer cohort, WBC and neutrophil counts were measured in average 7.1 years before cancer development. Cox-regression models were used to calculate hazard ratios (HRs) for VTE by WBC and neutrophil counts as categorized variables (<40th, 40-80th, and >80th percentile) with 95% confidence intervals (CIs).
During follow-up, 1720 subjects developed cancer and there were 388 VTE events, of which 116 occurred in the cancer-group (6.9 per 1000 person-years) and 272 in the cancer-free group (1.1 per 1000 person-years). In those who developed cancer, WBC count above the 80th percentile (≥8.6x109 cells/L) was associated with a 2.4-fold higher risk (HR 2.36, 95% CI: 1.44-3.87) of VTE compared to WBC count below the 40th percentile (<6.4x109 cells/L). No association was found between WBC count and VTE in those who stayed cancer-free (HR 0.94, 95% CI 0.65-1.36). Similar findings were observed for neutrophils.
Pre-cancer WBC count was associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that leukocytes may play a causal role in cancer-related VTE rather than only reflecting the low-grade inflammation associated with cancer.
PMCID: PMC3762748  PMID: 24023876
18.  White Blood Cell Count, C-Reactive Protein and Incident Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study 
Annals of epidemiology  2011;21(10):739-748.
To testthe hypothesis that inflammation measured by white blood cell count (WBC) and C-reactive protein (CRP) is associated positively with incident heart failure (HF).
Using the Atherosclerosis Risk in Communities (ARIC) Study, we conducted separate Cox proportional hazards regression analyses for WBC (measured 1987 to 1989) and CRP (measured 1996 to 1998) in relation to subsequent heart failure occurrence. A total of 14,485 and 9,978 individuals were included in the WBC and CRP analyses, respectively.
There were 1647 participants that developed HF during follow up after WBC assessment and 613 developed HF after CRP assessment. After adjustment for demographic variables and traditional HF risk factors, the hazard ratio (95% CI)for incident HF across quintiles of WBC was 1.0, 1.10 (0.9-1.34), 1.27(1.05-1.53), 1.44(1.19-1.74), and 1.62(1.34-1.96) (p trend <0.001); hazard ratio across quintiles of CRP was 1.0, 1.03 (0.68-1.55), 0.99 (0.66-1.51), 1.40 (0.94-2.09) and 1.70 (1.14-2.53) (p trend 0.002). Granulocytes appeared to drive the relation between WBCs and heart failure [hazard ratios across quintiles: 1.0, 0.93(0.76-1.15), 1.26 (1.04-1.53), 1.67(1.39-2.01) and 2.19 (1.83-2.61) (p trend <0.0001)], while lymphocytes or monocytes were not related.
Greater levels of WBC (especially granulocytes) and CRP are associated with increased risk of heart failure in middle-aged adults, independent of traditional risk factors.
PMCID: PMC3166412  PMID: 21784657
Prospective Study; Risk Factors; Heart Failure; Inflammation; C-Reactive Protein; Leukocytes; Granulocytes
19.  The Hematologic Profile of the Fetus with Systemic Inflammatory Response Syndrome 
Journal of Perinatal Medicine  2011;40(1):19-32.
The Fetal Inflammatory Response Syndrome (FIRS) is associated with the impending onset of preterm labor/delivery, microbial invasion of the amniotic cavity and increased perinatal morbidity. FIRS has been defined by an elevated fetal plasma interleukin-6 (IL-6), a cytokine with potent effects on the differentiation and proliferation of hematopoietic precursors. The objective of this study was to characterize the hematologic response of fetuses with FIRS.
Fetal blood sampling was performed in patients with preterm prelabor rupture of membranes and preterm labor with intact membranes (n=152). A fetal plasma IL-6 concentration >=11 pg/ml was used to define FIRS. Hemoglobin concentration, platelet count, total white blood cell (WBC) count, differential count and nucleated red blood cell (NRBC) count were obtained. Since blood cell count varies with gestational age, the observed values were corrected for fetal age by calculating a ratio between the observed and expected mean value for gestational age.
1) The prevalence of FIRS was 28.9% (44/152); 2) fetuses with FIRS had a higher median corrected WBC and corrected neutrophil count than those without FIRS (WBC median 1.4; range 0.3–5.6 vs. median 1.1; range 0.4–2.9 p=0.001; neutrophils median 3.6; range 0.1–57.5 vs. median 1.8; range 0.2–13.9 p<0.001); 3) neutrophilia (defined as a neutrophil count >95th centile of gestational age) was significantly more common in fetuses with FIRS than in those without FIRS [71% (30/42) vs. 35% (37/105); p<0 001]; 4) more than two thirds of fetuses with FIRS had neutrophilia, while neutropenia was present in only 4.8% (2/42); 5) FIRS was not associated with detectable changes in hemoglobin concentration, platelet, lymphocyte, monocyte, basophil or eosinophil counts and; 6) fetuses with FIRS had a median corrected NRBC count higher than those without FIRS. However, the difference did not reach statistical significance (NRBC median 0.07; range 0–1.3 vs. median 0.04; range 0–2.3 p=0.06);
The hematological response of the human fetus with FIRS is characterized by significant changes in the total white blood cell and neutrophil counts. The NRBC count in fetuses with FIRS tends to be higher than fetuses without FIRS.
PMCID: PMC3380620  PMID: 21957997
FIRS; preterm labor; preterm PROM; cordocentesis; neutrophil; nucleated red blood cells; infection; hypoxia; neutrophilia; neutropenia; white blood cell count
20.  White Blood Cells, Neutrophils, and Reactive Oxygen Metabolites among Asymptomatic Subjects 
Chronic inflammation and oxidative stress are associated with health and the disease status. The objective of the present study was to investigate the association among white blood cell (WBC) counts, neutrophil counts as a WBC subpopulation, and diacron reactive oxygen metabolites (d-ROMs) levels in an asymptomatic population.
The clinical data, including general cardiovascular risk variables and high-sensitivity C-reactive protein (hs-CRP), were collected from 100 female subjects (mean age, 62 years) in outpatient clinics. The correlation of the d-ROMs with hs-CRP, WBC, and neutrophil counts was examined.
The mean/median levels were WBC counts 5.9 × 109/L, neutrophil counts 3.6 × 109/L, hs-CRP 0.06 mg/dL, and d-ROMs 359 CURR U. A simple correlation analysis showed a significant positive correlation of the d-ROMs with the WBC counts, neutrophil counts, or hs-CRP levels. The correlation between d-ROMs and neutrophil counts (β = 0.22, P < 0.05), as well as that between d-ROMs and hs-CRP (β = 0.28, P < 0.01), remained significant and independent in a multiple linear regression analysis adjusted for other variables. A multiple linear regression analysis showed that WBC counts had only a positive correlation tendency to the d-ROMs.
Neutrophils may be slightly but more involved in the oxidative stress status, as assessed by d-ROMs, in comparison to the overall WBC. Further studies are needed to clarify the biologic mechanism(s) of the observed relationship.
PMCID: PMC3389441  PMID: 22783470
C-reactive protein; inflammation; leukocyte; neutrophil; oxidative stress
21.  White blood cell count and endothelin-1 vasoconstrictor tone in middle-aged and older adults 
Artery research  2012;6(2):65-70.
Higher white blood cell (WBC) count is associated with impaired endothelium-dependent vasodilation. However, the influence of higher WBC count on endothelin (ET)-1 vasoconstrictor activity is currently unknown. We tested the hypothesis that adults with elevated WBC count demonstrate enhanced ET-1 system activity.
Thirty-four healthy adults were studied: 17 with WBC count < 5.0 × 109 cells/L (lower WBC; 9M/8F; age: 53 ± 2 yr) and 17 with WBC count > 5.0 × 109 cells/L (higher WBC; 10M/7F; 54 ± 3 yr). Forearm blood flow (FBF) responses to intra-brachial infusion of ET-1 (5 pmol/min for 20 min) and selective ETA receptor blockade (BQ-123; 100 nmol/min for 60 min) were measured by venous occlusion plethysmography.
The vasoconstrictor response to ET-1 was significantly blunted (∼60%) in the higher WBC group versus the lower WBC group. The FBF responses to selective ETA receptor blockade were also significantly different (P < 0.05) between the groups. In the lower WBC group, resting FBF increased marginally (∼5%) to BQ-123, whereas the increase in FBF to BQ-123 was significantly greater (∼15%) in higher WBC group. Furthermore, there was a significant relation between WBC count and FBF response to ET-1 (r = −0.43) and BQ-123 (r = 0.41).
Relative elevations in WBC count in middle-aged and older adults, independent of adiposity and other cardiometabolic risk factors, are associated with enhanced ET-1-mediated vasoconstrictor tone. Elevated ET-1 system activity may be a mechanism linking higher WBC count with increased cardiovascular risk.
PMCID: PMC3727287  PMID: 23908675
Endothelin; Vasoconstriction; White blood cell
22.  Blood cell counts and their correlation with creatine kinase and C-reactive protein in patients with acute myocardial infarction 
This study reports differential blood cells counts and their correlations with creatine kinase (CK) and C-reactive protein (CRP) levels in acute myocardial infarction (AMI) patients and normal subjects. Peripheral blood samples were obtained from all 39 AMI patients and 35 controls for blood cell counts and CK and CRP analyses. Total WBC, WBC fractions, RBC and platelets were measured with an automated hematology analyzer. The results showed a significant increase in total WBC (8.688 × 109/L versus 6.148 × 109/L), monocytes (1.271 versus 0.497 × 109/L), and neutrophils (8.367 versus 3.223 × 109/L) counts in AMI patients than controls. The RBC count was significantly less in AMI patients (4.638 × 1012/L) as compared to controls (5.105 × 1012/L). However, there was no significant difference in lymphocytes, eosinophils, basophils and platelet counts between AMI patients and controls. Both, serum CK (215.38 ± 43.15 versus 100.82 ± 8.86 U/L) and CRP (29.49 ± 7.61 versus 3.48 ± 0.60 mg/L) were significantly higher in AMI patients as compared to controls. Age of the subjects was neither correlated with blood cell counts nor CK indicating the validity of these markers irrespective of patient age. A significant correlation was observed between WBC counts and CK (R = 0.242, P = 0.041) as well as CRP (R = 0.416, P = 0.000). In conclusion, this study clearly showed significant increase in total and differential leukocyte counts indicating a pro-inflammatory cascade in AMI patients. A significant correlation between WBC counts and CK or CRP levels suggest a possible biomarker value of WBC for a quick prediction of both myocardial necrosis and inflammation in AMI patients.
PMCID: PMC3272686  PMID: 22328948
Acute myocardial infarction; blood cells count; creatine kinase; inflammation; biomarker
23.  Association of inflammatory markers with colorectal cancer incidence in the Atherosclerosis Risk in Communities (ARIC) study 
Chronic inflammation has been implicated in the etiology of colorectal cancer (CRC), but epidemiological findings on the association between circulating inflammatory markers and CRC risk are inconsistent. We hypothesized that increased concentrations of systemic inflammatory markers – white blood cell count (WBC), fibrinogen, von Willebrand factor (VWF), factor VIII (FVIII), and C-reactive protein (CRP) – and decreased albumin concentration would be associated with increased CRC risk in the ARIC prospective cohort.
WBC, fibrinogen, VWF, FVIII, and albumin, measured in 1987–89 in 13,414 men and women, were transformed to Z scores and summed up to construct a blood “inflammation Z-score”. Albumin was included with a negative sign, since its concentration decreases with greater inflammation. A total of 308 incident CRC cases were identified through 2006 in initially cancer-free participants. CRP was measured in 1996–98 in 9,836 cancer-free people who developed 166 CRCs through 2006. Proportional hazard models were used to estimate the hazard ratios (HR) and (95% confidence interval, CI) of CRC in relation to each individual marker and the inflammation Z-score.
After multivariate adjustment, for the highest versus lowest quartile, there was a statistically significant positive association of CRC risk with fibrinogen: HR =1.50 (95%CI, 1.05;2.15) (p-trend across quartiles was 0.03), inflammation Z-score: HR=1.65 (95%CI, 1.15;2.35) (p-trend=0.01), and CRP: HR=1.97 (95%CI, 1.13;3.43) (p-trend=0.02).
These findings indicate that greater levels of fibrinogen, CRP, and blood inflammation Z-score are associated with increased CRC risk.
The study provides further evidence that pre-cancer inflammation may contribute to CRC etiology.
PMCID: PMC3169294  PMID: 21217085
acute-phase reactants; C-reactive protein; colorectal cancer; inflammation; prospective study
24.  Inflammation Biomarkers and Risk of All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke Cohort 
American Journal of Epidemiology  2011;174(3):284-292.
Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003–2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 × 109 cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (Ptrend < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers.
PMCID: PMC3202158  PMID: 21685411
biological markers; cohort studies; C-reactive protein; inflammation; leukocytes; mortality; prospective studies
25.  Relationship between Age and Peripheral White Blood Cell Count in Patients with Sepsis 
Total white blood cells (WBCs) decrease slightly in the elderly. In response to an acute infection, the number of WBCs increases and in sepsis, the increase is very dramatic. There are some reports about the effects of increased number of WBCs as a predisposing factor of bacteremia. An association between neutrophilia and eucopenia and increased mortality rate in the elderly has also been observed. We compared peripheral WBC counts in young and elderly patients with sepsis.
A case-control study was carried out on 130 admitted patients who were divided into two groups based on age, ≥ 65 years (case group) and < 65 years (control group). All patients were hospitalized with the diagnosis of sepsis in two teaching hospitals in Tehran, Iran, 2001-2006.
Mean WBC counts at admission time were 17061.5 ± 14240.2 /μl in the case group and 13567.7 ± 9888.0 /ml in the control group. There were statistically significant associations between age and history of infection and history of hospitalization during the last month in the case group and also between age and source of infection (P < 0.05).
The history of infection and the history of hospitalization during the last month with sepsis are important risk factors in elders.
PMCID: PMC3237266  PMID: 22174963
Sepsis; Leukocytosis; Elderly

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