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1.  A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation 
PLoS Medicine  2010;7(9):e1000341.
A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.
Background
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Conclusions
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Please see later in the article for the Editors' Summary
Editors' Summary
C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system). Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process. After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection. Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable. Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options. Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.
Why Was This Study Done?
Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis. Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.
What Did the Researchers Do and Find?
The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia. A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level. The relationship between genotype and serum CRP was explored by linear modeling. The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants. For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.
What Do These Findings Mean?
The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation. The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making. Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000341
Lab Test Online provides information on CRP
The Wellcome Trust provides a glossary of genetic terms
Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project
doi:10.1371/journal.pmed.1000341
PMCID: PMC2943443  PMID: 20877716
2.  Use of a Computerized C-Reactive Protein (CRP) Based Sepsis Evaluation in Very Low Birth Weight (VLBW) Infants: A Five-Year Experience 
PLoS ONE  2013;8(11):e78602.
Background
Serial C-reactive protein (CRP) values may be useful for decision-making regarding duration of antibiotics in neonates. However, established standard of practice for its use in preterm very low birth weight (<1500 g, VLBW) infants are lacking.
Objective
Evaluate compliance with a CRP-guided computerized decision support (CDS) algorithm and compare characteristics and outcomes of compliant versus non-compliant cases. Measure correlation between CRPs and white blood count (WBC) indices.
Methods
We examined 3 populations: 1) all preterm VLBW infants born at Vanderbilt 2006–2011 – we assessed provider compliance with CDS algorithm and measured relevant outcomes; 2) all patients with positive blood culture results admitted to the Vanderbilt NICU 2006–2012 – we tested the correlation between CRP and WBC results within 7 days of blood culture phlebotomy; 3) 1,000 randomly selected patients out of the 7,062 patients admitted to the NICU 2006–2012 – we correlated time-associated CRP values and absolute neutrophil counts.
Results
Of 636 VLBW infants in cohort 1), 569 (89%) received empiric antibiotics for suspected early-onset sepsis. In 409 infants (72%) the CDS algorithm was followed; antibiotics were discontinued ≤48 hours in 311 (55%) with normal serial CRPs and continued in 98 (17%) with positive CRPs, resulting in significant reduction in antibiotic exposure (p<0.001) without increase in complications or subsequent infections. One hundred sixty (28%) were considered non-compliant because antibiotics were continued beyond 48 hours despite negative serial CRPs and blood cultures. Serial CRPs remained negative in 38 (12%) of 308 blood culture-positive infants from cohort 2, but only 4 patients had clinically probable sepsis with single organisms and no immunodeficiency besides extreme prematurity. Leukopenia of any cell type was not linked with CRPs in cohorts 2 and 3.
Conclusions
CDS/CRP-guided antibiotic use is safe and effective in culture-negative VLBW infants. CRP results are not affected by low WBC indices.
doi:10.1371/journal.pone.0078602
PMCID: PMC3823853  PMID: 24244325
3.  C-Reactive Protein/Albumin Ratio Predicts 90-Day Mortality of Septic Patients 
PLoS ONE  2013;8(3):e59321.
Introduction
Residual inflammation at ICU discharge may have impact upon long-term mortality. However, the significance of ongoing inflammation on mortality after ICU discharge is poorly described. C-reactive protein (CRP) and albumin are measured frequently in the ICU and exhibit opposing patterns during inflammation. Since infection is a potent trigger of inflammation, we hypothesized that CRP levels at discharge would correlate with long-term mortality in septic patients and that the CRP/albumin ratio would be a better marker of prognosis than CRP alone.
Methods
We evaluated 334 patients admitted to the ICU as a result of severe sepsis or septic shock who were discharged alive after a minimum of 72 hours in the ICU. We evaluated the performance of both CRP and CRP/albumin to predict mortality at 90 days after ICU discharge. Two multivariate logistic models were generated based on measurements at discharge: one model included CRP (Model-CRP), and the other included the CRP/albumin ratio (Model-CRP/albumin).
Results
There were 229 (67%) and 111 (33%) patients with severe sepsis and septic shock, respectively. During the 90 days of follow-up, 73 (22%) patients died. CRP/albumin ratios at admission and at discharge were associated with a poor outcome and showed greater accuracy than CRP alone at these time points (p = 0.0455 and p = 0.0438, respectively). CRP levels and the CRP/albumin ratio were independent predictors of mortality at 90 days (Model-CRP: adjusted OR 2.34, 95% CI 1.14–4.83, p = 0.021; Model-CRP/albumin: adjusted OR 2.18, 95% CI 1.10–4.67, p = 0.035). Both models showed similar accuracy (p = 0.2483). However, Model-CRP was not calibrated.
Conclusions
Residual inflammation at ICU discharge assessed using the CRP/albumin ratio is an independent risk factor for mortality at 90 days in septic patients. The use of the CRP/albumin ratio as a long-term marker of prognosis provides more consistent results than standard CRP values alone.
doi:10.1371/journal.pone.0059321
PMCID: PMC3595283  PMID: 23555017
4.  Modeling effect of the septic condition and trauma on C-reactive protein levels in children with sepsis: a retrospective study 
Critical Care  2007;11(3):R70.
Introduction
Sepsis is the main cause of morbidity and mortality in intensive care units and its early diagnosis is not straightforward. Many studies have evaluated the usefulness of various markers of infection, including C-reactive protein (CRP), which is the most accessible and widely used. CRP is of weak diagnostic value because of its low specificity; a better understanding of patterns of CRP levels associated with a particular form of infection may improve its usefulness as a sepsis marker. In the present article, we apply multilevel modeling techniques and mixed linear models to CRP-related data to assess the time course of CRP blood levels in association with clinical outcome in children with different septic conditions.
Methods
We performed a retrospective analysis of 99 patients with systemic inflammatory response syndrome, sepsis, or septic shock who were admitted to the Pediatric Critical Care Unit at the University Hospital, Brno. CRP blood levels were monitored for 10 days following the onset of the septic condition. The effect of different septic conditions and of the surgical or nonsurgical diagnosis on CRP blood levels was statistically analyzed using mixed linear models with a multilevel modeling approach.
Results
A significant effect of septic condition and diagnosis on the course of CRP levels was identified. In patients who did not progress to septic shock, CRP blood levels decreased rapidly after reaching peak values – in contrast to the values in patients with septic shock in whom CRP protein levels decreased slowly. Moreover, CRP levels in patients with a surgical diagnosis were higher than in patients with a nonsurgical condition. The magnitude of this additional elevation in surgical patients did not depend on the septic condition.
Conclusion
Understanding the pattern of change in levels of CRP associated with a particular condition may improve its diagnostic and prognostic value in children with sepsis.
doi:10.1186/cc5955
PMCID: PMC2206436  PMID: 17598889
5.  Comparison of broad range 16S rDNA PCR and conventional blood culture for diagnosis of sepsis in the newborn: a case control study 
BMC Pediatrics  2009;9:5.
Background
Early onset bacterial sepsis is a feared complication of the newborn. A large proportion of infants admitted to the Neonatal Intensive Care Unit (NICU) for suspected sepsis receive treatment with potent systemic antibiotics while a diagnostic workup is in progress. The gold standard for detecting bacterial sepsis is blood culture. However, as pathogens in blood cultures are only detected in approximately 25% of patients, the sensitivity of blood culture is suspected to be low. Therefore, the diagnosis of sepsis is often based on the development of clinical signs, in combination with laboratory tests such as a rise in C – reactive protein (CRP). Molecular assays for the detection of bacterial DNA in the blood represent possible new diagnostic tools for early identification of a bacterial cause.
Methods
A broad range 16S rDNA polymerase chain reaction (PCR) without preincubation was compared to conventional diagnostic work up for clinical sepsis, including BACTEC blood culture, for early determination of bacterial sepsis in the newborn. In addition, the relationship between known risk factors, clinical signs, and laboratory parameters considered in clinical sepsis in the newborn were explored.
Results
Forty-eight infants with suspected sepsis were included in this study. Thirty-one patients were diagnosed with sepsis, only 6 of these had a positive blood culture. 16S rDNA PCR analysis of blinded blood samples from the 48 infants revealed 10 samples positive for the presence of bacterial DNA. PCR failed to be positive in 2 samples from blood culture positive infants, and was positive in 1 sample where a diagnosis of a non-septic condition was established. Compared to blood culture the diagnosis of bacterial proven sepsis by PCR revealed a 66.7% sensitivity, 87.5% specificity, 95.4% positive and 75% negative predictive value. PCR combined with blood culture revealed bacteria in 35.1% of the patients diagnosed with sepsis. Irritability and feeding difficulties were the clinical signs most often observed in sepsis. CRP increased in the presence of bacterial infection.
Conclusion
There is a need for PCR as a method to quickly point out the infants with sepsis. However, uncertainty about a bacterial cause of sepsis was not reduced by the PCR result, reflecting that methodological improvements are required in order for DNA detection to replace or supplement traditional blood culture in diagnosis of bacterial sepsis.
doi:10.1186/1471-2431-9-5
PMCID: PMC2635358  PMID: 19152691
6.  C-Reactive Protein, Detected with a Highly Sensitive Assay, in Non-Infected Newborns and Those with Early Onset Infection 
Summary
Backgound
The aim of this study was to investigate C-reactive protein (CRP), measured by a highly sensitive method (hsCRP) in non-infected newborns and in those with suspected early onset bacterial infection (EOBI) as well as to test whether EOBI would be detectable earlier by hsCRP than by a nephelometric CRP (nsCRP) assay (thresholds > 10 mg/l) or IL-8.
Patients and Methods
106 neonates with signs of infection comprised the suspected EOBI group. 134 neonates with risk factors but confirmed exclusion of EOBI served as non-infected controls.
Results
In the non-infected group, hsCRP in the first 6 h after birth was low (0.7 mg/l; SD 0.16 mg/l) but showed an increase to 4.11 mg/l (SD 3.33 mg/l) at 72 h (p < 0.001 vs. 6 h). The sensitivity of hsCRP (cut-off 0.3 mg/l) vs. nsCRP for EOBI was 0.46 vs. 0.23 at 6 h after clinical suspicion. Of all parameters measured, IL-8 had the highest sensitivity and specificity to detect EOBI at 6 h (0.60 and 0.90), but declined after 12 and 24 h.
Conclusion
Lowering the CRP detection threshold by a highly sensitive assay did not improve diagnostic accuracy for EOBI.
doi:10.1159/000112420
PMCID: PMC3083279  PMID: 21547109
Neonate; Infection; High sensitivity C-reactive protein
7.  Comparison of the accuracy of neutrophil CD64 and C-reactive protein as a single test for the early detection of neonatal sepsis 
Korean Journal of Pediatrics  2012;55(1):11-17.
Purpose
Early identification of neonatal sepsis is a global issue because of limitations in diagnostic procedures. The objective of this study was to compare the diagnostic accuracy of neutrophil CD64 and C-reactive protein (CRP) as a single test for the early detection of neonatal sepsis.
Methods
A prospective study enrolled newborns with documented sepsis (n=11), clinical sepsis (n=12) and control newborns (n=14). CRP, neutrophil CD64, complete blood counts and blood culture were taken at the time of the suspected sepsis for the documented or clinical group and at the time of venipuncture for laboratory tests in control newborns. Neutrophil CD64 was analyzed by flow cytometry.
Results
CD64 was significantly elevated in the groups with documented or clinical sepsis, whereas CRP was not significantly increased compared with controls. For documented sepsis, CD64 and CRP had a sensitivity of 91% and 9%, a specificity of 83% and 83%, a positive predictive value of 83% and 33% and a negative predictive value of 91% and 50%, respectively, with a cutoff value of 3.0 mg/dL for CD64 and 1.0 mg/dL for CRP. The area under the receiver-operating characteristic curves for CD64 index and CRP were 0.955 and 0.527 (P<0.01), respectively.
Conclusion
These preliminary data show that diagnostic accuracy of CD64 is superior to CRP when measured at the time of suspected sepsis, which implies that CD64 is a more reliable marker for the early identification of neonatal sepsis as a single determination compared with CRP.
doi:10.3345/kjp.2012.55.1.11
PMCID: PMC3282213  PMID: 22359525
Neutrophil CD64; C-reactive protein; Neonatal sepsis
8.  Positive Maternal C-Reactive Protein Predicts Neonatal Sepsis 
Yonsei Medical Journal  2013;55(1):113-117.
Purpose
To evaluate the diagnostic performance of maternal inflammatory marker: C-reactive protein (CRP) in predicting early onset neonatal sepsis (that occurring within 72 hours after birth).
Materials and Methods
126 low birth weight newborns (gestation 32±3.2 wk, birth weight 1887±623 g) and their mothers were included. Neonates were divided into sepsis group (n=51) including both proven (positive blood culture) and suspected (negative blood culture but with more than 3 abnormal clinical signs), and controls (n=75). Mothers were subgrouped into CRP positive ≥1.22 mg/dL (n=48) and CRP negative <1.22 mg/dL (n=78) group, determined by Receiver Operating Characteristic curves, and odds ratio was calculated for neonatal sepsis according to maternal condition.
Results
Maternal CRP was significantly higher in neonatal sepsis group than in control (3.55±2.69 vs. 0.48±0.31 mg/dL, p=0.0001). Maternal CRP (cutoff value >1.22 mg/dL) had sensitivity 71% and specificity 84% for predicting neonatal sepsis. Maternal CRP positive group had more neonatal sepsis than CRP negative group (71% vs. 29%, p<0.001). Odds ratio of neonatal sepsis in maternal CRP positive group versus CRP negative group was 10.68 (95% confidence interval: 4.313-26.428, p<0.001).
Conclusion
The risk of early onset neonatal sepsis significantly increased in the case of positive maternal CRP (≥1.22 mg/dL). In newborn of CRP positive mother, the clinician may be alerted to earlier evaluation for possible neonatal infection prior to development of sepsis.
doi:10.3349/ymj.2014.55.1.113
PMCID: PMC3874922  PMID: 24339295
Neonatal sepsis; chorioamnionitis; maternal C-reacitve protein
9.  Levels of soluble ICAM-1 in premature and full-term neonates with infection. 
Mediators of Inflammation  2002;11(2):95-98.
BACKGROUND: Infection in the neonatal period is an extremely serious condition and diagnosis is difficult. C-reactive protein (CRP) is widely used as a marker of infection; however, its usefulness is limited in the early phase. The role of soluble intracellular adhesion molecule-1 (sICAM-1), an adhesion molecule, has been examined in recent studies as an early marker of neonatal infection with controversial results. AIM: Assessment of sICAM-1 concentrations and correlation with CRP, which is the currently used marker of infection, in order to use sICAM as an early diagnostic tool in neonates suspected for infection METHODS: Blood samples and blood cultures were obtained from two groups of pre-term and full-term neonates with clinical suspicion of infection prior to the initiation of antibiotics. The sICAM-1 and CRP values were compared with the corresponding noninfected ones (n = 10 each). RESULTS: The sICAM-1 levels were found increased in the group of both premature and term neonates with infection compared with the corresponding healthy ones (P < 0.0001). Prematurity combined with infection resulted in excessive increase of the levels of sICAM-1 in comparison with full-term infected newborns (p < 0.001). CRP values were normal in all samples except one in both full-term and premature infected neonates on day 1 of clinically suspected infection. Serial detection of CRP values on days 2 and 4 of infection revealed a pattern according to which CRP values in premature neonates continued rising, while in the group of full terms these values, after rising on the second day, lowered on day 4. CONCLUSIONS: Increased sICAM-1 levels can be detected early in both full-term and premature neonates with sepsis while CRP levels are within normal range at the same time. Assessment of sICAM-1 concentrations may be used as a diagnostic tool in neonates suspected for infection, resulting in earlier initiation of antibiotic therapy and therefore improving their outcome.
PMCID: PMC1781652  PMID: 12061430
10.  Management of neonatal sepsis at Muhimbili National Hospital in Dar es Salaam: diagnostic accuracy of C – reactive protein and newborn scale of sepsis and antimicrobial resistance pattern of etiological bacteria 
BMC Pediatrics  2014;14(1):293.
Background
We determined the accuracy of Rubarth’s newborn scale of sepsis and C- reactive protein in diagnosing neonatal sepsis and assessed antimicrobial susceptibility pattern of etiological bacteria.
Methods
This cross sectional study was conducted at Muhimbili National Hospital in Dar es Salaam, Tanzania between July 2012 and March 2013. Neonates suspected to have sepsis underwent physical examination using Rubarth’s newborn scale of sepsis (RNSOS). Blood was taken for culture and antimicrobial sensitivity testing, full blood picture and C – reactive protein (CRP) performed 12 hours apart. The efficacy of RNSOS and serial CRP was assessed by calculating sensitivity, specificity, negative and positive predictive values, receiver operating characteristics (ROC) analysis as well as likelihood ratios (LHR) with blood culture result used as a gold standard.
Results
Out of 208 blood samples, 19.2% had a positive blood culture. Single CRP had sensitivity and specificity of 87.5% and 70.9% respectively, while RNSOS had sensitivity of 65% and specificity of 79.7%. Serial CRP had sensitivity of 69.0% and specificity of 92.9%. Combination of CRP and RNSOS increased sensitivity to 95.6% and specificity of 56.4%. Combination of two CRP and RNSOS decreased sensitivity to 89.1% but increased specificity to 74%. ROC for CRP was 0.86; and for RNSOS was 0.81.
For CRP the LHR for positive test was 3 while for negative test was 0.18, while for RNSOS the corresponding values were 3.24 and for negative test was 0.43.
Isolated bacteria were Klebsiella spp 14 (35%), Escherichia coli 12 (22.5%), Coagulase negative staphlococci 9 (30%), Staphylococcus aureus 4 (10%), and Pseudomonas spp 1 (2.5%). The overall resistance to the WHO recommended first line antibiotics was 100%, 92% and 42% for cloxacillin, ampicillin and gentamicin, respectively. For the second line drugs resistance was 45%, 40%, and 7% for ceftriaxone, vancomycin and amikacin respectively.
Conclusions
Single CRP in combination with RNSOS can be used for rapid identification of neonates with sepsis due to high sensitivity (95.6%) but cannot exclude those without sepsis due to low specificity (56.4%). Serial CRP done 12hrs apart can be used to exclude non-cases. This study demonstrated very high levels of resistance to the first-line antibiotics.
doi:10.1186/s12887-014-0293-4
PMCID: PMC4262228  PMID: 25475836
C – Reactive protein; Newborn scale of sepsis; Hematological markers; Neonatal sepsis
11.  Mark B. Coventry Award: Synovial C-reactive Protein: A Prospective Evaluation of a Molecular Marker for Periprosthetic Knee Joint Infection 
Background
C-reactive protein (CRP) serum assays are a standard element of the diagnostic workup for periprosthetic joint infection (PJI). However, because CRP is a marker for systemic inflammation, this test is not specific to PJI.
Questions/purposes
Our purpose was to assess whether synovial fluid and serum assays alone could differentiate between infected and uninfected revision knee arthroplasties and to determine which of these methods had the greatest diagnostic accuracy.
Methods
We collected synovial fluid specimens from 66 patients undergoing revision total knee arthroplasty. Patients were judged uninfected or infected by standardized criteria. Synovial CRP levels were measured using an individual CRP assay (15 samples; 10 infected, five uninfected) and a multiplex immunoassay platform (59 samples; 25 infected, 34 uninfected). Results from preoperative standard serum CRP assays conducted were also collected (55 samples; 25 infected, 30 uninfected). Sensitivity, specificity, and receiver operating characteristic curve analyses were performed for each assay with a diagnosis of infection based on previously established criteria.
Results
Synovial CRP concentrations differed between infected and uninfected joints in the multiplex and serum analyses. The area under the curve was 0.84 for the individual assay, 0.91 for the multiplex assay, and 0.88 for the serum CRP assay. Sensitivity and specificity were 70.0% and 100.0% for the individual enzyme-linked immunosorbent assay, 84.0% and 97.1% for the multiplex assay, and 76.0% and 93.3% for the serum CRP assay.
Conclusions
An assay measuring CRP in synovial fluid may be more accurate in diagnosing PJI than the standard serum CRP assay. We believe such an assay holds promise as a new diagnostic marker for PJI.
Level of Evidence
Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-011-1991-y
PMCID: PMC3237977  PMID: 21786056
12.  Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream 
PLoS Medicine  2008;5(8):e155.
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal.
Editors' Summary
Background.
Diabetes—a common, long-term (chronic) disease that causes heart, kidney, nerve, and eye problems and shortens life expectancy—is characterized by high levels of sugar (glucose) in the blood. In people without diabetes, blood sugar levels are controlled by the hormone insulin. Insulin is released by the pancreas after eating and “instructs” insulin-responsive muscle and fat cells to take up the glucose from the bloodstream that is produced by the digestion of food. In the early stages of type 2 diabetes (the commonest type of diabetes), the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance), and blood sugar levels increase. The pancreas responds by making more insulin—people with insulin resistance have high blood levels of both insulin and glucose. Eventually, however, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and frank diabetes develops.
Why Was This Study Done?
Globally, about 200 million people have diabetes, but experts believe this number will double by 2030. Ways to prevent or delay the onset of diabetes are, therefore, urgently needed. One major risk factor for insulin resistance and diabetes is being overweight. According to one theory, increased body fat causes mild, chronic tissue inflammation, which leads to insulin resistance. Consistent with this idea, people with higher than normal amounts of the inflammatory protein C-reactive protein (CRP) in their blood have a high risk of developing diabetes. If inflammation does cause diabetes, then drugs that inhibit CRP might prevent diabetes. However, simply measuring CRP and determining whether the people with high levels develop diabetes cannot prove that CRP causes diabetes. Those people with high blood levels of CRP might have other unknown factors in common (confounding factors) that are the real causes of diabetes. In this study, the researchers use “Mendelian randomization” to examine whether increased blood CRP causes diabetes. Some variants of CRP (the gene that encodes CRP) increase the amount of CRP in the blood. Because these variants are inherited randomly, there is no likelihood of confounding factors, and an association between these variants and the development of insulin resistance and diabetes indicates, therefore, that increased CRP levels cause diabetes.
What Did the Researchers Do and Find?
The researchers measured blood CRP levels in more than 5,000 people enrolled in the Whitehall II study, which is investigating factors that affect disease development. They also used the “homeostasis model assessment-insulin resistance” (HOMA-IR) method to estimate insulin sensitivity from blood glucose and insulin measurements, and measured levels of hemoglobin A1c (HbA1c, hemoglobin with sugar attached—a measure of long-term blood sugar control) in these people. Finally, they looked at three “single polynucleotide polymorphisms” (SNPs, single nucleotide changes in a gene's DNA sequence; combinations of SNPs that are inherited as a block are called haplotypes) in CRP in each study participant. Common haplotypes of CRP were related to blood serum CRP levels and, as previously reported, increased blood CRP levels were associated with diabetes and with HOMA-IR and HbA1c values indicative of insulin resistance and poor blood sugar control, respectively. By contrast, CRP haplotypes were not related to HOMA-IR or HbA1c values. Similarly, pooled analysis of CRP haplotypes and diabetes in Whitehall II and another large study on health determinants (the Northwick Park Heart Study II) showed no association between CRP variants and diabetes risk. Finally, data from the Wellcome Trust Case Control Consortium also showed no association between CRP haplotypes and diabetes risk.
What Do These Findings Mean?
Together, these findings suggest that increased blood CRP levels are not responsible for the development of insulin resistance or diabetes, at least in European populations. It may be that there is a causal relationship between CRP levels and diabetes risk in other ethnic populations—further Mendelian randomization studies are needed to discover whether this is the case. For now, though, these findings suggest that drugs targeted against CRP are unlikely to prevent or delay the onset of diabetes. However, they do not discount the possibility that proteins involved earlier in the inflammatory process might cause diabetes and might thus represent good drug targets for diabetes prevention.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050155.
This study is further discussed in a PLoS Medicine Perspective by Bernard Keavney
The MedlinePlus encyclopedia provides information about diabetes and about C-reactive protein (in English and Spanish)
US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on all aspects of diabetes, including information on insulin resistance (in English and Spanish)
The International Diabetes Federation provides information about diabetes, including information on the global diabetes epidemic
The US Centers for Disease Control and Prevention provides information for the public and professionals on all aspects of diabetes (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050155
PMCID: PMC2504484  PMID: 18700811
13.  A prospective study of the sensitivity, specificity and diagnostic performance of soluble intercellular adhesion molecule 1, highly sensitive C-reactive protein, soluble E-selectin and serum amyloid A in the diagnosis of neonatal infection 
BMC Pediatrics  2010;10:22.
Background
Diagnosis of neonatal infection is difficult, because of it's non-specific clinical presentation and the lack of reliable diagnostic tests. The purpose of this study was to examine the potential diagnostic value of serum soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin), highly sensitive C-reactive protein (hsCRP) and serum amyloid A (SAA) measurements, both individually and in combination in the setting of a neonatal intensive care unit.
Methods
219 consecutive serum samples were taken from 149 infants undergoing sepsis work up in a neonatal intensive care unit. Clinical diagnosis was established in a prospective manner, blind to the results of the study measurements. Infants were classified by an experienced paediatrician as infected or not-infected, one week after presentation. Classification was based on clinical presentation, routine laboratory and radiological investigations and response to therapy. The infected group were sub-classified as (a) culture positive infection or (b) culture negative infection. sICAM-1, sE-selectin, hsCRP and SAA levels were determined from stored serum samples after diagnosis was established. Further sub-group analysis of results was undertaken according to early or late onset of infection and preterm or term status. Statistical analysis utilised Mann Whitney U test and ROC curve analysis.
Results
There were significantly increased serum levels of sICAM-1, hsCRP, E selectin (p < 0.001) and SAA (p = 0.004) in infected infants compared with non-infected. ROC curve analysis indicated area under the curve values of 0.79 (sICAM-1), 0.73 (hsCRP), 0.72 (sE-selectin) and 0.61 (SAA). ROC curve analysis also defined optimum diagnostic cut-off levels for each measurement. The performance characteristics of sICAM-1, hsCRP and sE-selectin included a high negative predictive value (NPV) for culture positive infection and this was enhanced by combination of all 4 measurements. Clinical subgroup analysis suggested particularly high NPV for early onset symptoms, however further studies are required to elucidate this finding.
Conclusions
All four study measurements demonstrated some diagnostic value for neonatal infection however sICAM-1, hsCRP and sE-selectin demonstrated the highest NPV individually. The optimum diagnostic cut off level for hsCRP measurement in this study was much lower than currently used in routine clinical practice. Use of a combination of measurements enhanced diagnostic performance, demonstrating sensitivity of 90.3% and NPV of 91.3%. This study suggests there may be value in use of several of these markers, individually and in combination to assist in excluding neonatal infection. Further work is needed to confirm a specific role in the exclusion of early onset infection.
doi:10.1186/1471-2431-10-22
PMCID: PMC2868836  PMID: 20398379
14.  Neonatal infections in Saudi Arabia: association with C-reactive protein, CRP -286 (C>T>A) gene polymorphism and IgG antibodies 
BMC Immunology  2013;14:38.
Background
C-reactive protein (CRP) is a nonspecific, acute-phase protein that rises in response to infectious and non-infectious inflammatory processes. Infections are the single largest cause of neonatal deaths globally.
The primary aim of this study is to examine the association between CRP gene polymorphism and serum levels of CRP in correlation with early onset sepsis (EOS) infection in newborns living in Taif city, Saudi Arabia. The second aim is to examine the relationship between specific IgG/IgG subclasses and early onset sepsis (EOS) infection among these newborns.
Methods
Staphylococcus aureus (S. aureus) is one of the most common organisms related to sepsis infection in the newborn at King Abdel Aziz Specialist Hospital (KAASH). This study was conducted in Taif city, at KAASH’s neonatal intensive care unit between March and August 2012. Neonates were consecutively enrolled onto the study having met our inclusion criteria (as per our research protocol).
The CRP concentration level was analysed using NycoCard® CRP Single Test. CRP -286 (C>T>A) A polymorphisms were analyzed using Pyrosequencing technology for CRP genotyping. IgG subclasses were analysed in the study population using ELISA.
Result
Logistic regression analyses showed that the AA and AC genotypes were negatively associated amongst EOS neonates compared to suspected neonates. The frequency of CC and CT were significantly associated with the EOS neonates compared to the suspected group. The levels of specific IgG1, IgG2 and IgG3 antibodies were significantly lower amongst EOS compared to the suspected group.
Conclusions
Taken together, the CRP-286 (C>T>A) A genotype polymorphism and specific IgG antibodies isotype levels can contribute to a reduced risk of EOS. Furthermore, CRP has a potential use in detecting EOS in neonates, which may mean earlier detection and management of EOS and subsequently better clinical outcome.
doi:10.1186/1471-2172-14-38
PMCID: PMC3751442  PMID: 23941472
CRP; CRP gene Polymorphism; IgG subclasses; Early onset sepsis (EOS); Saudi Arabia
15.  Improving diagnostic accuracy of bacterial pharyngitis by near patient measurement of C-reactive protein (CRP) 
BACKGROUND: Sore throat or pharyngitis is an extremely prevalent condition in primary care. There is a diagnostic dilemma in differentiating bacterial and non-bacterial infections for adequate use of antibiotics. Standard diagnostic procedures take too long for an immediate decision. AIM: To evaluate, if near patient C-reactive protein measurement in the general practice surgery improves diagnostic accuracy. METHOD: One hundred and seventy-nine consecutive patients with sore throat, from 15 general practitioners (GPs) in southern Germany (phase 1) and 161 consecutive patients from 14 GPs (phase 2), were examined physically and a throat-swab was taken and white blood-cell count (WBC) and CRP-measurement were performed. In phase 1, CRP was measured centrally to assess the method's diagnostic value and the adequate threshold. In the second phase, near patient CRP was measured and CRP values were used to make a diagnosis. RESULTS: Using relative operating characteristics (ROC) analysis, the diagnostic value of CRP measurement was much better than WBC count (area under curve = 0.85 versus 0.68). All diagnostic parameters improved when using the near patient CRP measurement. Sensitivity went up from 0.61 (95% confidence interval = 0.45-0.75) to 0.78 (0.61-0.90), specificity went up from 0.73 (0.65-0.81) to 0.82 (0.73-0.88). Positive and negative predictive value improved significantly as well. Diagnostic accuracy went up from 70.1% to 81.0%. Out of 1000 theoretical patients with sore throat, 109 more will be treated correctly when using CRP measurement as a diagnostic tool. CONCLUSIONS: Use of near patient CRP measurement can improve diagnostic accuracy in the differentiation of bacterial and non-bacterial pharyngitis in primary care, and potentially results in a more adequate use of antibiotics.
PMCID: PMC1313346  PMID: 10326264
16.  Diagnostic Accuracy of the Quantitative C-Reactive Protein, Erythrocyte Sedimentation Rate and White Blood Cell Count in Urinary Tract Infections among Infants and Children 
Objectives:
The aim of this study was to evaluate the diagnostic accuracy of the quantitative C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count in urinary tract infections (UTI) among hospitalised infants and children in Qazvin, Iran.
Methods:
This cross-sectional study was conducted on 127 hospitalised children ranging in age from 2 months to 12 years old 31.79 months (SD 30.73) who were suspected of having a UTI and who did not receive antibiotics prior to being seen at a Qazvin teaching children’s hospital between 2005 and 2006. A urine analysis (U/A) and urine culture (U/C) were performed. The blood was taken for CRP, ESR and WBC analyses. U/C has been considered the gold standard test for a UTI and dimercaptosuccinic acid renal scintigraphy (DMSA) as the gold standard for an upper UTI (pyelonephritis). These tests were used to determine the diagnostic accuracy, which is represented as the percent of correct results.
Results:
Within the study population, 72 patients (56.7%) were younger than two years old 9.86 months (SD 4.56) and 55 (43.3%) were older than two years old 63.58 months (SD 30.96). One hundred and two patients (80.3%) were female. There were 100 cases that had a positive U/C. Of the patients with a positive U/C, 81 had pyuria (WBC more than 5/hpf), 71 had a peripheral WBC count of more than 10 000 /mL, 95 had a CRP of more than 10 mg/L and 82 had an ESR > 10 mm/h. The sensitivity and specificity as well as the positive and negative predictive values and the accuracy of CRP when using U/C as the gold standard were, respectively, 96%, 11.1%, 80.2%, 50%, and 78%; when using ESR as the gold standard were, respectively, 55%, 40%, 77.6%, 17.2%, and 52%; and when using WBC counts as the gold standard were, respectively, 69%, 52%, 86.6%, 35.6%, and 65%. The accuracy of CRP, ESR and WBC counts when considering the DMSA as the gold standard were 58.3%, 62.8%, and 64.5%, respectively.
Conclusion:
Although acute phase reactants can help in the diagnosis of a UTI, they are not pathognomonic. CRP, ESR and WBC were neither completely sensitive nor specific for detecting a UTI and its localisation site in Iranian children. Therefore, in a country where advanced clinical diagnostic tests are available, the advanced test should be used in conjunction with CRP, ESR and WBC analyses. Finally, a combination of laboratory tests along with history and exact clinical examination are needed for the diagnosis of a UTI and its localisation site.
PMCID: PMC3957355  PMID: 24643248
children; DMSA renal scintigraphy; erythrocyte sedimentation rate; Urinary tract infection; quantitative C-reactive protein
17.  Serum procalcitonin as a diagnostic marker of neonatal sepsis 
Korean Journal of Pediatrics  2014;57(10):451-456.
Purpose
We evaluated serum procalcitonin (PCT) as a diagnostic marker of neonatal sepsis, and compared PCT levels with C-reactive protein (CRP) levels.
Methods
We retrospectively reviewed the medical records of 269 neonates with a suspected infection, admitted to Wonkwang University School of Medicine & Hospital between January 2011 and December 2012, for whom PCT and CRP values had been obtained. Neonates were categorized into 4 groups according to infection severity. CRP and PCT values were analyzed and compared, and their effectiveness as diagnostic markers was determined by using receiver operating characteristic (ROC) curve analysis. We also calculated the sensitivity, specificity, and positive, and negative predictive values.
Results
The mean PCT and CRP concentrations were respectively 56.27±81.89 and 71.14±37.17 mg/L in the "confirmed sepsis" group; 15.64±32.64 and 39.23±41.41 mg/L in the "suspected sepsis" group; 9.49±4.30 and 0.97±1.16 mg/L in the "mild infection" group; and 0.21±0.12 and 0.72±0.7 mg/L in the control group. High concentrations indicated greater severity of infection (P<0.001). Five of 18 patients with confirmed sepsis had low PCT levels (<1.0 mg/L) despite high CRP levels. In the ROC analysis, the area under the curve was 0.951 for CRP and 0.803 for PCT. The cutoff concentrations of 0.5 mg/L for PCT and 1.0 mg/L for CRP were optimal for diagnosing neonatal sepsis (sensitivity, 88.29% vs. 100%; specificity, 58.17% vs. 85.66%; positive predictive value, 13.2% vs. 33.3%; negative predictive value, 98.6% vs. 100%, respectively).
Conclusion
PCT is a highly effective early diagnostic marker of neonatal infection. However, it may not be as reliable as CRP.
doi:10.3345/kjp.2014.57.10.451
PMCID: PMC4219948  PMID: 25379046
Sepsis; Procalcitonin; C-reactive protein
18.  Utility of qualitative C- reactive protein assay and white blood cells counts in the diagnosis of neonatal septicaemia at Bugando Medical Centre, Tanzania 
BMC Pediatrics  2014;14(1):248.
Background
Neonatal septicaemia diagnosis based on clinical features alone is non-specific leading to the initiation of unnecessary antibiotic treatment posing a danger of increased antibiotic resistance. In the present study the utility of serial qualitative C-reactive protein (CRP) assay and white blood cells count (WBC) in the diagnosis of neonatal septicaemia was investigated using blood culture as gold standard.
Methods
A total of 305 neonates admitted at Bugando Medical Centre (BMC) neonatal units between September 2013 and April 2014 were enrolled. Demographic and clinical data were collected using standardized data collection tool. Blood specimens were collected for blood culture, WBC count and qualitative CRP assay.
Results
Of 305 neonates; 224 (73.4%) were ≤ 72 hrs of age and 91(29.8%) had low birth weight. The positive CRP assay was observed in 67 (22.0%), 80 (26.2%) and 88 (28.9%) of neonates on day 1, 2 and 3 respectively; with any CRP positive occurred in 104 (34.1%) of neonates. The sensitivities of CRP assay in the diagnosis of septicaemia using culture as gold standard on day 1, 2, 3 and any positive were 40.4%, 53.2%, 54.8% and 62.9% respectively. While specificities were 82.7%, 80.7%, 77.8% and 73.3% respectively. Higher sensitivity of 75% was observed when CRP was used to diagnose gram negative septicaemia compared to 50% that was observed in the diagnosis of gram positive septicaemia. WBC count of ≥13 × 109 /L had sensitivity and specificity of 64.5% and 66.7% respectively with area under the curve of 0.694. When the any positive CRP and WBC of ≥13 × 109 /L were used the sensitivity increased to 90.3% with specificity of 50%. Neonates with septicaemia due to gram negative bacteria were significantly found to have higher rates of positive CRP than neonates with gram positive septicaemia and with negative culture (p < 0.001, OR 8.2, 95 CI; 2.9-26).
Conclusion
In place where blood culture is limited neonates having clinical features of neonatal sepsis with positive qualitative CRP assay and increased WBC should urgently be initiated on appropriate sepsis management in order to reduce morbidity and mortality associated with neonatal sepsis.
doi:10.1186/1471-2431-14-248
PMCID: PMC4192733  PMID: 25280754
C-reactive protein; Neonatal sepsis; WBC
19.  High-mobility group box-1 protein, lipopolysaccharide-binding protein, interleukin-6 and C-reactive protein in children with community acquired infections and bacteraemia: a prospective study 
Introduction
Even though sepsis is one of the common causes of children morbidity and mortality, specific inflammatory markers for identifying sepsis are less studied in children. The main aim of this study was to compare the levels of high-mobility group box-1 protein (HMGB1), Lipopolysaccharide-binding protein (LBP), Interleukin-6 (IL-6) and C-reactive protein (CRP) between infected children without systemic inflammatory response syndrome (SIRS) and children with severe and less severe sepsis. The second aim was to examine HMGB1, LBP, IL6 and CRP as markers for of bacteraemia.
Methods
Totally, 140 children with suspected or proven infections admitted to the Children's Clinical University Hospital of Latvia during 2008 and 2009 were included. Clinical and demographical information as well as infection focus were assessed in all patients. HMGB1, LBP, IL-6 and CRP blood samples were determined. Children with suspected or diagnosed infections were categorized into three groups of severity of infection: (i) infected without SIRS (n = 36), (ii) sepsis (n = 91) and, (iii) severe sepsis (n = 13). They were furthermore classified according bacteraemia into (i) bacteremia (n = 30) and (ii) no bacteraemia (n = 74).
Results
There was no statistically significant difference in HMGB1 levels between children with different levels of sepsis or with and without bacteraemia. The levels of LBP, IL-6 and CRP were statistically significantly higher among patients with sepsis compared to those infected but without SIRS (p < 0.001). Furthermore, LBP, IL-6 and CRP were significantly higher in children with severe sepsis compared to those ones with less severe sepsis (p < 0.001). Median values of LBP, IL6 and CRP were significantly higher in children with bacteraemia compared to those without bacteraemia. The area under the receiver operating curve (ROC) for detecting bacteraemia was 0.87 for both IL6 and CRP and 0.82 for LBP, respectively.
Conclusion
Elevated levels of LBP, IL-6 and CRP were associated with a more severe level of infection in children. Whereas LBP, IL-6 and CRP seem to be good markers to detect patients with bacteraemia, HMGB1 seem to be of minor importance. LBP, IL-6 and CRP levels may serve as good biomarkers for identifying children with severe sepsis and bacteraemia and, thus, may be routinely used in clinical practice.
doi:10.1186/1471-2334-10-28
PMCID: PMC2831899  PMID: 20158885
20.  C-reactive protein measurement in general practice may lead to lower antibiotic prescribing for sinusitis 
Background: Symptoms of bacterial sinusitis overlap with viral sinusitis, and it is difficult to distinguish between the two conditions based only on a clinical examination. Uncertain diagnosis results in the significant overuse of antibiotics, which is considered to be one of the most important reasons for development of bacterial resistance to antibiotics. A raised C-reactive protein (CRP) level is an indicator of bacterial infection and the CRP rapid test has been shown to be useful for the diagnosis of bacterial sinusitis in general practice.
Aims: To examine whether general practitioners (GPs) who use the CRP rapid test in their practice have a lower antibiotic prescribing rate for sinusitis than GPs who do not use the test.
Design of study: Observational design.
Setting: General practice in Denmark.
Method: A group of GPs registered all contacts (n = 17 792) with patients who had respiratory tract infections during a 3-week period between 1 November 2001 and 31 January 2002. GPs who used a CRP rapid test were compared with GPs who did not, and the treatment of their patients (n = 1444) with suspected sinusitis was compared.
Results: A CRP rapid test was used by 77% (n = 281) of the GPs. In the group of GPs using a CRP rapid test, the rate of antibiotic prescribing was 59% (95% confidence interval [CI] = 56 to 62) compared with 78% (95% CI = 73 to 82) in the group of GPs who did not use a CRP test. Performing a CRP rapid test was the factor that exerted the greatest influence on whether the patients were prescribed antibiotics, and the level of CRP had a strong influence on the prescribing rate.
Conclusion: The CRP rapid test has a substantial influence on the treatment of sinusitis, and implementing the test in general practice may lead to a reduction in antibiotic prescribing to patients with sinusitis.
PMCID: PMC1326065  PMID: 15353050
antibiotics; C-reactive protein; general practice; sinusitis
21.  CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients 
Introduction
Single-nucleotide polymorphisms (SNPs) in the CRP gene are implicated in the regulation of the constitutional C-reactive protein (CRP) expression and its response to proinflammatory stimuli. Previous reports suggest that these effects may have an impact on clinical decision-making tools based on CRP, such as the Disease Activity Score in 28 joints (DAS28). We aimed to investigate the possible association between seven CRP SNPs, their haplotypes and the serum levels of CRP, as well as DAS28 scores, in two cohorts of untreated active early rheumatoid arthritis (RA) patients followed during their initial treatment.
Methods
Overall, 315 patients with RA from two randomized controlled trials (the CIMESTRA and OPERA trials) who were naïve to disease-modifying antirheumatic drugs and steroids with disease durations less than 6 months were included. Seven CRP SNPs were investigated: rs11265257, rs1130864, rs1205, rs1800947, rs2808632, rs3093077 and rs876538. The genotype and haplotype associations with CRP and DAS28 levels were evaluated using linear regression analysis adjusted for age, sex and treatment.
Results
The minor allele of rs1205 C > T was associated with decreased CRP levels at baseline (P = 0.03), with the TT genotype having a 50% reduction in CRP from 16.7 to 8.4 mg/L (P = 0.005) compared to homozygosity of the major allele, but no association was observed at year 1 (P = 0.38). The common H2 haplotype, characterized by the T allele of rs1205, was associated with a 26% reduction in CRP at baseline (P = 0.043), although no effect was observed at year 1 (P = 0.466). No other SNP or haplotype was associated with CRP at baseline or at year 1 (P ≥0.09). We observed no associations between SNPs or haplotypes and DAS28 scores at baseline or at year 1 (P ≥0.10).
Conclusion
CRP genotype and haplotype were only marginally associated with serum CRP levels and had no association with the DAS28 score. This study shows that DAS28, the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.
Trial registration
The OPERA study is registered at Clinicaltrials.gov (NCT00660647). The CIMESTRA study is not listed in a clinical trials registry, because patients were included between October 1999 and October 2002.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0475-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-014-0475-3
PMCID: PMC4247621  PMID: 25359432
22.  The course of C-reactive protein response in untreated upper respiratory tract infection 
Background: High C-reactive protein (CRP) values are frequently found in patients with bacterial respiratory infection, and CRP testing has been shown to be useful in differentiating pneumonia from other respiratory infections. Raised CRP values may also be found in viral respiratory infection, and as a result there is a risk that antibiotics may be wrongly prescribed.
Aims: To describe the course of the CRP response during untreated upper respiratory tract infections and associations between the development of CRP values, erythrocyte sedimentation rate (ESR) and respiratory symptoms.
Design of study: Prospective study.
Setting: Seven general practices in northern Norway.
Method: Patients with upper respiratory tract infection aged 16 years or over, who were not treated with antibiotics and who had been ill for no more than 3 days, were recruited. Microbiological examinations were undertaken, together with measurements of CRP, ESR and recording of symptoms daily during the first week of illness and on days 10, 14 and 21.
Results: An aetiological agent was established in 23 of the 41 included subjects. These were: influenza A, influenza B, rhinovirus, and other agents. Among the 15 patients examined on both the second and the third day of illness, the median CRP value increased from 7–10 mg/l, and the mean value was from 19–24 mg/l between day 2 and day 3. Peak CRP values were reached on days 2 to 4. Higher CRP values were found in those infected with influenza A and B than in the other subjects (P<0.001). A CRP value >10 mg/l was found in 26 subjects during the first 7 days, compared to five subjects after 1 week. Evidence of a secondary infection with group A streptococci was found in two of these five subjects. The development of the symptoms of sore throat, fatigue, clamminess, and pain from muscles and joints followed a similar course as the CRP response, while stuffy nose, cough, sputum production, and dyspnoea tended to persist after the CRP values had approached the normal range.
Conclusion: A moderately elevated CRP value (10–60 mg/l) is a common finding in viral upper respiratory tract infection, with a peak during days 2–4 of illness. Moderately elevated CRP values cannot support a diagnosis of bacterial infection when the illness has lasted less than 7 days, but may indicate a complication of viral infection after a week.
PMCID: PMC1326064  PMID: 15353049
antibiotics; common cold; cough; C-reactive protein; erythrocyte sedimentation rate; influenza; upper respiratory infections
23.  Cumulative Depression Episodes Predicts Later C-Reactive Protein Levels: A Prospective Analysis 
Biological psychiatry  2011;71(1):15-21.
Background
Depression is associated with elevated levels of the inflammation marker C -reactive protein (CRP), yet the direction of this association remains unclear. This study tested bi-directional longitudinal associations between CRP and depression in a sample of adolescent and young adults. The study compared the effects of current depression to the cumulative episodes of depression over time.
Methods
Nine waves of data from the prospective population-based Great Smoky Mountains Study (N = 1,420) were used, covering children in the community aged 9–16, 19, and 21 years old. Structured interviews were used to assess depressive symptoms, depression diagnosis, and cumulative depressive episodes. Bloodspots were collected at each observation and assayed for CRP levels.
Results
CRP levels were not associated with later depression status. In contrast, all depression-related variables displayed evidence of association with later CRP levels. The associations with depressive symptoms and diagnostic status were attenuated after controlling for covariates particularly body mass index, smoking, and medication use. The effect of cumulative depressive episodes, however, continued to be significant after accounting for a range of covariates. Body mass index, smoking behavior and recent infections may mediate a portion of the effect of cumulative episodes on later CRP, but cumulative depressive episodes continued to predict CRP levels independently.
Conclusions
The occurrence of multiple depressive episodes exerted the greatest effect on later CRP levels. This suggests that risk for the diseases of middle age - cardiovascular and metabolic disease – may begin in childhood and depend, in part, upon long-term emotional functioning.
doi:10.1016/j.biopsych.2011.09.023
PMCID: PMC3586231  PMID: 22047718
Inflammation; CRP; Depression; Epidemiology; Childhood; Adolescence
24.  Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction 
Critical Care  2004;8(4):R234-R242.
Introduction
Both C-reactive protein (CRP) and procalcitonin (PCT) are accepted sepsis markers. However, there is still some debate concerning the correlation between their serum concentrations and sepsis severity. We hypothesised that PCT and CRP concentrations are different in patients with infection or with no infection at a similar severity of organ dysfunction or of systemic inflammatory response.
Patients and methods
One hundred and fifty adult intensive care unit patients were observed consecutively over a period of 10 days. PCT, CRP and infection parameters were compared among the following groups: no systemic inflammatory response syndrome (SIRS) (n = 15), SIRS (n = 15), sepsis/SS (n = 71) (including sepsis, severe sepsis and septic shock [n = 34, n = 22 and n = 15]), and trauma patients (n = 49, no infection).
Results
PCT and CRP concentrations were higher in patients in whom infection was diagnosed at comparable levels of organ dysfunction (infected patients, regression of median [ng/ml] PCT = -0.848 + 1.526 sequential organ failure assessment [SOFA] score, median [mg/l] CRP = 105.58 + 0.72 SOFA score; non-infected patients, PCT = 0.27 + 0.02 SOFA score, P < 0.0001; CRP = 84.53 - 0.19 SOFA score, P < 0.005), although correlation with the SOFA score was weak (R = 0.254, P < 0.001 for PCT, and R = 0.292, P < 0.001 for CRP). CRP levels were near their maximum already during lower SOFA scores, whereas maximum PCT concentrations were found at higher score levels (SOFA score > 12).
PCT and CRP concentrations were 1.58 ng/ml and 150 mg/l in patients with sepsis, 0.38 ng/ml and 51 mg/l in the SIRS patients (P < 0.05, Mann–Whitney U-test), and 0.14 ng/ml and 72 mg/l in the patients with no SIRS (P < 0.05). The kinetics of both parameters were also different, and PCT concentrations reacted more quickly than CRP.
Conclusions
PCT and CRP levels are related to the severity of organ dysfunction, but concentrations are still higher during infection. Different sensitivities and kinetics indicate a different clinical use for both parameters.
doi:10.1186/cc2877
PMCID: PMC522844  PMID: 15312223
calcitonin; C-reactive protein; infection; procalcitonin; sepsis; sequential organ failure assessment score; systemic inflammatory response syndrome
25.  Estimating the Impact of Adding C-Reactive Protein as a Criterion for Lipid Lowering Treatment in the United States 
Background
There is growing interest in using C-reactive protein (CRP) levels to help select patients for lipid lowering therapy—although this practice is not yet supported by evidence of benefit in a randomized trial.
Objective
To estimate the number of Americans potentially affected if a CRP criteria were adopted as an additional indication for lipid lowering therapy. To provide context, we also determined how well current lipid lowering guidelines are being implemented.
Methods
We analyzed nationally representative data to determine how many Americans age 35 and older meet current National Cholesterol Education Program (NCEP) treatment criteria (a combination of risk factors and their Framingham risk score). We then determined how many of the remaining individuals would meet criteria for treatment using 2 different CRP-based strategies: (1) narrow: treat individuals at intermediate risk (i.e., 2 or more risk factors and an estimated 10–20% risk of coronary artery disease over the next 10 years) with CRP > 3 mg/L and (2) broad: treat all individuals with CRP > 3 mg/L.
Data source
Analyses are based on the 2,778 individuals participating in the 1999–2002 National Health and Nutrition Examination Survey with complete data on cardiac risk factors, fasting lipid levels, CRP, and use of lipid lowering agents.
Main measures
The estimated number and proportion of American adults meeting NCEP criteria who take lipid-lowering drugs, and the additional number who would be eligible based on CRP testing.
Results
About 53 of the 153 million Americans aged 35 and older meet current NCEP criteria (that do not involve CRP) for lipid-lowering treatment. Sixty-five percent, however, are not currently being treated, even among those at highest risk (i.e., patients with established heart disease or its risk equivalent)—62% are untreated. Adopting the narrow and broad CRP strategies would make an additional 2.1 and 25.3 million Americans eligible for treatment, respectively. The latter strategy would make over half the adults age 35 and older eligible for lipid-lowering therapy, with most of the additionally eligible (57%) coming from the lowest NCEP heart risk category (i.e., 0–1 risk factors).
Conclusion
There is substantial underuse of lipid lowering therapy for American adults at high risk for coronary disease. Rather than adopting CRP-based strategies, which would make millions more lower risk patients eligible for treatment (and for whom treatment benefit has not yet been demonstrated in a randomized trial), we should ensure the treatment of currently defined high-risk patients for whom the benefit of therapy is established.
doi:10.1007/s11606-006-0033-z
PMCID: PMC1824732  PMID: 17356986
coronary disease; risk assessment; C-reactive protein; antilipemic agents; guideline adherence

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