High-Sensitivity C-Reactive Protein and Risk of Sepsis
Henry E. Wang1*, Nathan I. Shapiro2, Monika M. Safford3, Russell Griffin4, Suzanne Judd5,
Joel B. Rodgers1, David G. Warnock6, Mary Cushman7, George Howard5
1Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America, 2Department of Emergency Medicine,
Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America, 3Division of Preventive Medicine, Department of Medicine, University of Alabama
School of Medicine Birmingham, Alabama, United States of America, 4Department of Epidemiology, School of Public Health, University of Alabama at Birmingham,
Birmingham, Alabama, United States of America, 5Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama,
United States of America, 6Division of Nephrology, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America,
7Division of Hematology and Oncology, Department of Medicine, University of Vermont, Burlington, Vermont, United States of America
Background: Conventional C-reactive protein assays have been used to detect or guide the treatment of acute sepsis. The
objective of this study was to determine the association between elevated baseline high-sensitivity C-reactive protein
(hsCRP) and the risk of future sepsis events.
Methods: We studied data from 30,239 community dwelling, black and white individuals, age $45 years old enrolled in the
REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Baseline hsCRP and participant characteristics
were determined at the start of the study. We identified sepsis events through review of hospital records. Elevated hsCRP
was defined as values .3.0 mg/L. Using Cox regression, we determined the association between elevated hsCRP and first
sepsis event, adjusting for sociodemographic factors (age, sex, race, region, education, income), health behaviors (tobacco
and alcohol use), chronic medical conditions (coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney
disease, chronic lung disease) and statin use.
Results: Over the mean observation time of 5.7 years (IQR 4.5–7.1), 974 individuals experienced a sepsis event, and 11,447
(37.9%) had elevated baseline hsCRP (.3.0 mg/L). Elevated baseline hsCRP was independently associated with subsequent
sepsis (adjusted HR 1.56; 95% CI 1.36–1.79), adjusted for sociodemographics, health behaviors, chronic medical conditions
and statin use.
Conclusion: Elevated baseline hsCRP was associated with increased risk of future sepsis events. hsCRP may help to identify
individuals at increased risk for sepsis.
Citation: Wang HE, Shapiro NI, Safford MM, Griffin R, Judd S, et al. (2013) High-Sensitivity C-Reactive Protein and Risk of Sepsis. PLoS ONE 8(7): e69232.
Editor: Irving Coy Allen, Virginia Tech University, United States of America
Received April 19, 2013; Accepted June 6, 2013; Published July 23, 2013
Copyright: ? 2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by award R01-NR012726 from the National Institute for Nursing Research, UL1-RR025777 from the National Center for
Research Resources, as well as by grants from the Center for Clinical and Translational Science and the Lister Hill Center for Health Policy of the University of
Alabama at Birmingham. The parent REGARDS study was supported by cooperative agreement U01-NS041588 from the National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not
necessarily represent the official views of the funding agencies. Representatives of the funding agencies have been involved in the review of the manuscript but
not directly involved in the collection, management, analysis or interpretation of the data.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Sepsis, the syndrome of microbial infection complicated by
systemic inflammatory response, is a major public health problem
associated with significant morbidity and mortality.  The
national burden of severe sepsis care in the United States is
substantial, encompassing an estimated 750,000 hospital admis-
sions, 570,000 Emergency Department visits, 200,000 deaths and
$16.7 billion in medical expenditures annually.[2–4] While efforts
to reduce the public health impact of sepsis have focused primarily
on optimizing hospital outcomes after the onset of disease, there
has been relative little attention directed towards identifying its
antecedent risk factors. [5,6]
Biomarkers have been broadly used to aid in the diagnosis,
prognostication or therapy of many medical conditions.  C-
reactive protein (CRP) is an acute phase protein that plays a
prominent role in many diseases. Elevated CRP levels detected
using high-sensitivity assay techniques have been associated with
risk of cardiovascular disease, stroke and all-cause mortality.[7–9]
While often used to detect or guide the treatment of acute sepsis,
there have been few efforts linking CRP level at a stable phase of
health with risk of future sepsis events.[10–18] As with cardiovas-
cular disease, if baseline CRP levels were associated with future
sepsis events, this finding could motivate strategies to mitigate
disease severity or mortality, or to prevent the onset of the
The objective of this study was to determine the association
between baseline high-sensitivity CRP (hsCRP) and future risk of
sepsis in community-dwelling individuals.
PLOS ONE | www.plosone.org1 July 2013 | Volume 8 | Issue 7 | e69232
Materials and Methods
This study was approved by the Institutional Review Board of
the University of Alabama at Birmingham with waiver of the
requirement for informed consent.
This study utilized data from the Reasons for Geographic and
Racial Differences in Stroke (REGARDS) cohort, a national
population-based longitudinal cohort.
Selection of Participants
Designed to evaluate geographic and black-white stroke
mortality variations, REGARDS is one of the largest ongoing
national cohorts of community-dwelling individuals in the US,
encompassing 30,239 individuals $45 years old.  REGARDS
includes individuals from all regions of the continental US.
Participant representation oversampled the Southeastern US, with
20% of the cohort originating from the coastal plains of North
Carolina, South Carolina and Georgia (the ‘‘buckle’’ of the stroke
belt), and 30% originating from the remainder of North Carolina,
South Carolina and Georgia plus Tennessee, Mississippi, Ala-
bama, Louisiana and Arkansas (the ‘‘stroke belt’’). The cohort is
41% African American and 45% male, and 69% of individuals are
.60 years old. The cohort does not include Hispanics where
stroke mortality disparities are small to non-existent.
REGARDS enrolled participants during 2003–7. REGARDS
obtained baseline data for each participant using both phone
interview and in-person evaluations. Baseline data included
medical history, functional status, health behaviors, physical
characteristics (height, weight), physiologic measures (blood
pressure, pulse, electrocardiogram), and an inventory of medica-
tions. Each participant provided blood and urine specimens. Self-
administered questionnaires evaluated diet, family history of
diseases, psychosocial factors and prior residences. On a semi-
annual basis, the study contacted each participant to determine
the date, location and attributed reason for all emergency
department visits and hospitalizations during the follow-up
interval. If the participant died, the study team reviewed death
certificates and medical records and interviewed proxies to
ascertain the circumstances of the participant’s death.
Identification of Sepsis Events
Using a taxonomy for serious infections developed by Angus,
et al., we reviewed all reported hospital admissions and Emergen-
cy Department visits attributed by participants to a serious
infection.  Two trained abstractors independently reviewed all
relevant medical records to confirm the presence of a serious
infection on initial hospital presentation, and the relevance of the
serious infection as a major reason for hospitalization. The
abstractors identified clinical and laboratory information from the
first 28-hours of hospitalization. The abstractors adjudicated
discordances, with additional physician-level review as needed.
Consistent with international consensus definitions, sepsis
consisted of presentation to the hospital with an infection plus
two or more systemic inflammatory response syndrome (SIRS)
criteria, including 1) heart rate .90 beats/minute, 2) fever
(temperature .38.3uC or ,36uC), 3) tachypnea (.20 breaths/
min) or PCO2,32 mmHg, and 4) leukocytosis (white blood cells
[WBC] .12,000 or ,4,000 cells/mm3or .10% band forms). 
Presentation to the hospital consisted of the time of Emergency
Department triage or admission to inpatient unit (for participants
admitted directly to the hospital). To allow for acute changes in the
participant’s condition during early hospitalization, we used vital
signs and laboratory test results for the initial 28-hours of
hospitalization. We did not include vital signs or laboratory
findings at later time points of the hospitalization. We did not
include sepsis developing at later time points of the hospitalization.
We did not include organ dysfunction in the definition of sepsis.
Initial review of 1,349 hospital records indicated excellent inter-
rater agreement for presence of a serious infection (kappa=0.92)
and the presence of sepsis (kappa=0.90) upon hospital presenta-
Measurement of Baseline hsCRP
Trained personnel collected blood samples from all REGARDS
participants at subjects’ homes following a 10–12 hour fast.
Samples were centrifuged and serum or plasma separated within 2
hours of collection (mean 97 minutes, SD 127 minutes) and
shipped overnight on ice packs to the central laboratory at the
University of Vermont. Overnight shipping of samples was
achieved for 95% of the cohort. On arrival, samples were
centrifuged at 30,000 g and 4uC, and either analyzed (general
chemistries) or stored at 280uC. hsCRP was determined in
batches by particle-enhanced immunonephelometry using the
BNII nephelometer (N High-sensitivity CRP; Dade Behring) with
interassay CVs of 2.1%–5.7%. There was no difference in hsCRP
distribution by number of sample shipping days. In contrast with
conventional CRP assays, the high-sensitivity CRP technique is
able to detect levels as low as 0.04 mg/L.
We considered covariates correlated with hsCRP including
sociodemographic characteristics, health behaviors and chronic
medical conditions.  Sociodemographic characteristics includ-
ed age, sex, race, geographic region, self-reported annual
household income and self-reported education (years of school).
Geographic region was defined as participant residence in the
stroke ‘‘buckle,’’ stroke ‘‘belt,’’ and elsewhere.  Health
behaviors included tobacco and alcohol use. Smoking status use
was defined as current, past and never. We defined alcohol use
according to the National Institute on Alcohol Abuse and
Alcoholism classification; i.e., moderate (1 drink per day for
women or 2 drinks per day for men) and heavy alcohol use (.1
drink per day for women and .2 drinks per day for men). 
Evaluated chronic medical conditions included hypertension,
diabetes, dyslipidemia, coronary artery disease, chronic kidney
disease, and chronic lung disease. Hypertension consisted of
systolic blood pressure $140 mm Hg, diastolic blood pressure
$90 mm Hg, or the reported use of antihypertensive agents.
Diabetes included a fasting glucose $126 mg/L (or a glucose
$200 mg/L for those not fasting) or the use of insulin or oral
hypoglycemic agents. Dyslipidemia consisted of low density
lipoprotein cholesterol .130 mg/dL, or use of lipid lowering
medications. A history of coronary artery disease consisted of
individuals with a self-reported history of myocardial infarction,
coronary intervention or baseline electrocardiographic evidence of
Chronic kidney disease consisted of an estimated glomerular
filtration rate ,60 ml/min/1.73 m2calculated using the CKD-
EPI equation.  Because REGARDS did not collect informa-
tion on pulmonary conditions such as asthma and chronic
obstructive pulmonary disease, we defined participant use of
pulmonary medications as a surrogate for chronic lung disease.
Obtained from each participant’s medication inventory, pulmo-
nary medications included beta agonists, leukotriene inhibitors,
inhaled corticosteroids, combination inhalers, and other pulmo-
hsCRP and Sepsis
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nary medications such as ipratropium, cromolyn, aminophylline
and theophylline. We also identified statin use through the
participant’s medication inventory.
To maintain consistency with cardiovascular studies, we defined
elevated baseline hsCRP as .3.0 mg/L.  We compared
demographic, health behavioral and clinical characteristics
between individuals with normal and elevated hsCRP. Using
Cox proportional hazards regression, we calculated hazard ratios
(HR) and 95% confidence intervals (CI) for the association
between elevated baseline hsCRP and first episode of sepsis during
follow-up. We defined person-time at risk as the time (days) from
first in-person examination to the first episode of sepsis or the last
follow-up interview, whichever came first. We adjusted the models
for demographic characteristics (age, sex, race, education,
geographic region, income), health behaviors (smoking and
alcohol use), and chronic medical conditions (hypertension,
dyslipidemia, coronary artery disease, chronic kidney disease,
chronic lung disease). Because statins lower inflammatory markers,
we also adjusted for statin use. 
Due to the time lag in observations and medical record
retrieval, we could not review medical records for 1,157
participants with reported hospitalizations for a serious infection
over the observation period (2003–2011), a figure expected to yield
an additional 300 sepsis events based on adjudication rates for
other participants. Therefore, we repeated the analysis excluding
these individuals. The primary analysis focused on sepsis events. In
a secondary analysis we examined the association between hsCRP
and non-sepsis infection events (serious infections that did not
fulfill SIRS criteria). We conducted all analyses using SAS v9.3.
Among the 30,239 REGARDS participants, from February 5,
2003 through July 30, 2012, we identified 2,151 hospitalizations
for a serious infection, encompassing 1,179 sepsis events among
974 individuals. Mean follow-up time was 5.7 years (IQR 4.5–7.1).
Among participants with available values, median hsCRP was
2.2 mg/L (IQR 1.0, 5.0), and 11,447 (37.9%) exhibited elevated
hsCRP (.3.0 mg/L). Among the 974 sepsis individuals with
hsCRP levels available, the most common infection types
associated with the first sepsis episode were pneumonia, kidney
and urinary tract infections, and abdominal infections. (Table 1)
Individuals with elevated hsCRP were more likely to be younger,
female, or black, and to report lower income and education.
(Table 2) While individuals with elevated hsCRP were more likely
to be current or past smokers, they were less likely to report heavy
or moderate alcohol use. Chronic medical conditions were more
common in individuals with elevated hsCRP.
Among REGARDS participants, 491 of 18,736 (2.6%) individ-
uals with hsCRP#3.0 mg/L developed sepsis, and 483 of 11,447
(4.2%) with CRP.3.0 mg/L developed sepsis. Elevated baseline
hsCRP (.3.0 mg/L) was independently associated with an
increased risk of sepsis (HR 1.68; 95% CI: 1.48–1.90). (Table 3)
Elevated baseline hsCRP remained independently associated with
sepsis risk after adjustment for demographic characteristics, health
behaviors, chronic medical conditions and statin use (HR 1.56;
95% CI 1.36–1.79). (Table 3).
When repeating the analysis excluding the 1,157 participants
with unadjudicated potential sepsis events, there was a similar
association between CRP and incident sepsis (adjusted HR 1.51;
95% CI 1.31–1.76). Excluded individuals were less likely to be
African American (39.6 vs. 41.5%) and exhibited slightly higher
hsCRP levels (mean 5.4 vs. 4.6 mg/L). In a secondary analysis we
identified 828 individuals with non-sepsis infection events (serious
infections that did not fulfill SIRS criteria). While elevated baseline
hsCRP was independently associated with the risk of non-sepsis
infection events (adjusted HR 1.37; 95% CI: 1.18–1.60), the
relationship was lower than that for sepsis events.
Elevated hsCRP levels detected using high-sensitivity assay
techniques have been associated with risk of cardiovascular
disease, stroke and all-cause mortality.[7–9] In this study of
individuals in the REGARDS cohort, we found that elevated
baseline hsCRP was associated with increased risk of future sepsis
events. This finding suggests that knowledge of hsCRP level could
help to identify individuals at increased risk for sepsis.
There are plausible pathophysiologic connections between
elevated baseline hsCRP and future sepsis events. CRP is believed
to activate complement, interact with cell surface receptors, induce
a prothrombotic state, increase expression of inflammatory
mediators, and upregulate endothelial cell adhesion molecules,
among other actions.  Many of the same inflammatory
Table 1. Infection types associated with hospitalizations for sepsis.
Infection TypeNumber of Sepsis Hospitalizations (n=974) N (%)
Kidney and Urinary Tract Infections157 (16.1)
Abdominal 136 (14.0)
Bronchitis, Influenza and other Lung Infections 89 (9.1)
Skin and Soft Tissue 74 (7.6)
Sepsis 58 (6.0)
Fever of Unknown Origin15 (1.5)
Surgical Wound7 (0.7)
Catheter (IV/Central/Dialysis)5 (0.5)
Meningitis 3 (0.3)
Includes first sepsis episodes only.
hsCRP and Sepsis
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Table 2. Baseline characteristics of subjects with normal #3.0 mg/L and elevated .3.0 mg/L baseline high-sensitivity C-reactive
hsCRP# #3.0 mg/L
hsCRP. .3.0 mg/L
68–75 24.0 22.3
Less than high school10.815.6
High school graduate24.827.7
College or higher38.3 28.9
$20 k–$34 k
$35 k–$74 k
Geographic Region (%)
Stroke Buckle20.3 21.9
Tobacco Use (%)
Alcohol Use (%)
Moderate 35.9 29.0
CHRONIC MEDICAL CONDITIONS
Chronic Kidney Disease (%)23.2 27.1
Chronic Lung Disease (%)8.0 11.2
Coronary Artery Disease (%)17.6 18.60.03
Diabetes (%) 19.625.8
Dyslipidemia (%)34.6 31.8
Hypertension (%) 54.866.7
Statin use (%)32.9 28.9
*Based on chi-square test.
hsCRP and Sepsis
PLOS ONE | www.plosone.org4 July 2013 | Volume 8 | Issue 7 | e69232
processes also play key roles in sepsis. [2,26] For example, we
previously identified associations between inflammatory and
endothelial activation biomarkers and future sepsis events. 
Collectively, these observations suggest that elevated hsCRP may
signal individuals with a chronic low-grade proinflammatory state
and prone to the hyperinflammatory state characteristic of sepsis.
An important question requiring additional study is whether
hsCRP exerts a direct effect upon sepsis susceptibility or represents
a marker of the inflammatory process that is causal in increasing
Prior studies have associated acute CRP increases (on the order
of 10–200 mg/dL) as a marker of sepsis illness severity as well as
predicted of sepsis outcomes.[10–18] For example, in a series of 50
critically ill sepsis patients, Schmit, et al. observed that CRP on
hospital admission was 16.7610.6 mg/dL and that the magnitude
of CPR decrease was associated with response to antimicrobial
therapy.  Povoa, et al. studied 891 intensive care unit patients
with community-acquired sepsis, observing a mean hospital
admission CRP level of 20.1613.9 mg/dL and finding association
between rates of CRP decline and hospital survival.  In
contrast, our findings are based upon levels determined at a stable
phase of health using a high-sensitivity CRP assay, which detects
levels as low as 0.04 mg/L. In addition, we focused upon the
association between baseline hsCRP levels and risk of future sepsis
events – not the acute course of illness.
Prior studies have examined the association between CRP levels
and infection risk. For example, in a case-control study of 144
patients with HIV infection, Bjerk, et al. found that higher hsCRP
was associated with a two-fold increased odds ratio for pneumonia.
 In a study of 3,075 elderly (.70 years old) participants in the
Health ABC cohort, Yende, et al. found that higher baseline CRP
levels were not independently associated with pneumonia risk. 
However, Yende’s effort did not utilize the newer high sensitivity
CRP assay, as we used in the current study. We note that in the
current study we did identify an independent association between
baseline hsCRP and non-sepsis infection risk. While we did not
separately examine pneumonia cases, over half of the sepsis cases
in this series were due to lung infections.
We emphasize that we did not set out to develop a sepsis risk
prediction rule using hsCRP. Our study merely indicates the
presence of an association between hsCRP and future sepsis risk.
However, given the results of this study, hsCRP may potentially
play a role in a formal derivation of a risk prediction model. If the
risk predictive abilities of hsCRP were validated, there could be
plausible strategies to reduce the risk or impact of sepsis. For
example, individuals at high risk of sepsis may merit more
proactive treatment at the earliest stages of microbial infection,
with earlier initiation of antibiotics, reduced thresholds for hospital
admission, more aggressive early resuscitation, or more vigilant
laboratory and physiologic monitoring during hospitalization.
Statin therapy reduces cardiovascular events in individuals with
elevated baseline hsCRP.  Gupta, et al. showed that statin use
was associated with a reduced risk of hospitalization for sepsis
among individuals with chronic kidney disease.  Other studies
of hospitalized sepsis patients have suggested mitigated disease
severity and organ dysfunction among those with pre-existing
statin use. 
Limitations of this study should be noted. To maintain
consistency with prior cardiovascular studies, in this study we
defined elevated baseline hsCRP as .3.0 mg/L.  However,
other hsCRP cutpoints are potentially possible for different age,
sex or racial groups and merit additional study. Due to time lags in
event reports and record retrieval, we have not yet reviewed
medical records for a portion of individuals with reported serious
infection hospitalizations. Furthermore, compared with individuals
included in the analysis, excluded individuals were more likely to
be black and to exhibit higher hsCRP levels. Therefore, our
reported HRs may represent underestimates. Because REGARDS
is not a surveillance study, we may not have detected all sepsis
events. We did not examine severity variants of sepsis such as
severe sepsis and septic shock because these conditions often
develop later in the hospital course; however, it is possible that
associations between hsCRP and various forms of sepsis may differ
than those reported here. We also did not examine associations
between hsCRP and repeat sepsis events.
By design, the REGARDS cohort includes only African
Americans and whites, and thus we could not examine associations
among other racial groups or Hispanic ethnicity. History of cancer
was not ascertained by REGARDS, and this may represent an
important risk factor for subsequent sepsis. Also, our study was
able to detect the presence of chronic medical conditions but not
their level of severity. Because the study did not collect information
on pulmonary conditions, we used pulmonary medications as a
surrogate for chronic lung disease. Our analysis utilized baseline
hsCRP measurements; we could not assess the effect of changes of
hsCRP over time. While we observed an association between
elevated hsCRP and sepsis risk, elevated hsCRP may reflect risk
for a host of inflammatory conditions not limited to sepsis; for
example, cardiovascular disease and stroke. [8,9]
In this study elevated hsCRP at a stable phase of health was
associated with increased risk of future sepsis events. hsCRP may
identify individuals at increased risk for sepsis.
Table 3. Hazard ratios (HRs) and 95% confidence intervals (CI) for the adjusted associations between elevated baseline high-
sensitivity C-reactive protein (hsCRP.3.0 mg/L) and first sepsis episodes.
ModelN Events Hazard Ratio (95% CI)
Crude (unadjusted) HR 29,667972 1.68 (1.48–1.90)
Adjusted for age, sex, race, region29,667 972 1.86 (1.64–2.12)
Additional adjustment for education and income29,644970 1.77 (1.56–2.01)
Additional adjustment for smoking and alcohol use28,959940 1.70 (1.50–1.94)
Additional adjustment for chronic medical conditions* and statin use26,999 8811.56 (1.36–1.79)
Total of 30,183 REGARDS participants included in the analysis.
*Coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney disease, chronic lung disease.
hsCRP and Sepsis
PLOS ONE | www.plosone.org5 July 2013 | Volume 8 | Issue 7 | e69232
Acknowledgments Download full-text
The authors thank the investigators, the staff, and the participants of the
REGARDS study for their valuable contributions. A full list of
participating REGARDS investigators, institutions and study staff can be
found at http://www.regardsstudy.org and http://www.regardssepsis.org.
Presented at Society for Critical Care Medicine Annual Congress,
January 2013, Puerto Rico.
Conceived and designed the experiments: HEW NIS MMS GH. Analyzed
the data: RG HEW. Wrote the paper: HEW. Coordinated data collection:
HEW MMS RG JBR. Contributed to the review and interpretation of
results: HEW NIS MMS RG SJ JBR DGW MC GH. Contributed to the
critical revision and final approval of the manuscript: HEW NIS MMS RG
SJ JBR DGW MC GH.
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