Erythrocyte Sedimentation Rate and C-Reactive Protein

E r y t h ro c y t e Se d i m e n t a t i o n R a t e a n d C - R e a c t i v e Pro t e i n Aaron J. Calderon,

MD

a,b,

*, Mark H. Wener,

MD

c,d,e

KEYWORDS  Erythrocyte sedimentation rate  C-reactive protein  High-sensitivity CRP  Acute-phase reactant  Inflammatory biomarker  Disease activity  Response to therapy  Sepsis

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Recognize the erythrocyte sedimentation rate (ESR) as an indirect measurement of acute-phase proteins that responds slowly to inflammatory stimuli, and the C-reactive protein (CRP) test as a direct acute-phase protein measurement that responds very quickly. 2. Recognize that the ESR is affected by multiple factors whereas CRP is only affected by the presence and degree of inflammation. 3. Adjust the maximum normal Westergren ESR for age by using the following formulas: in men, upper limit of the reference range equals age in years/2, and in women, upper limit of the reference range equals (age in years 1 10)/2. 4. Adjust the maximum normal CRP level for age by using the following formulas: upper limit of the reference range in mg/L equals (age in years)/5 for men and (age in years/5) 1 6 for women. 5. Be aware that CRP levels reported in mg/dL are 10 times lower than when reported as mg/L. CONTINUED

a

Internal Medicine Residency, Exempla Saint Joseph Hospital, Denver, CO, USA; b University of Colorado Denver School of Medicine, Aurora, CO, USA; c Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; d Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA; e Clinical Laboratory, University of Washington Medical Center, Seattle, WA, USA * Corresponding author. Internal Medicine Residency, Exempla Saint Joseph Hospital, 1835 Franklin Street, Denver, CO 80218. E-mail address: [email protected]

Hosp Med Clin 1 (2012) e313–e337 doi:10.1016/j.ehmc.2012.02.002 2211-5943/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.

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CONTINUED

6. Use ESR and CRP judiciously to rule out certain disorders when the pretest likelihood of disease is low or moderate. The ESR and CRP are of lower diagnostic utility in ruling in disease, as they are not specific for any particular disease. 7. Realize that CRP levels of 10 to 100 mg/L are usually representative of mild to moderate infections (viral or bacterial) or connective tissue disorders, and malignancy. CRP levels above 100 mg/L strongly point to a bacterial infection. 8. Recognize extreme elevation of the ESR (100 mm/h) as almost always a hallmark of serious underlying disease, most commonly malignancy, infection, or connective tissue disease. 9. Always use ESR and CRP in conjunction with the clinical context. Both ESR and CRP are helpful in determining disease activity and response to therapy, but they must be used in combination with a detailed history, physical examination, and other key studies. 10. When comparing with the ESR, rely on CRP as the more accurate and more rapidly responsive inflammatory biomarker, and the preferred marker ordered in the acute hospital setting for evaluating and monitoring infection or inflammation. Consider using the ESR when following patients with chronic inflammation. 11. Avoid ordering an ESR and CRP in tandem, although the combination may be helpful in certain circumstances. 12. Do not use high-sensitivity (hs)-CRP in the acute setting to determine longterm cardiovascular risk.

1. What is C-reactive protein? C-reactive protein (CRP) is valued clinically as a sensitive marker of inflammation. CRP levels in young healthy adults are usually less than 10 mg/L, but can increase as much as 10,000-fold in response to infection or inflammation.1 CRP is a member of the pentraxin protein family, whose members are characterized by having 5 repeating subunits with a flat (planar) pentagonal shape.1 Other pentraxins include serum amyloid P (named because it is contained in amyloid deposits) and pentraxin-3, another acute-phase protein. This protein family is highly conserved in evolution, suggesting that CRP has an important physiologic role.2 The molecular mass of CRP is 115 kDa. CRP is a component of the innate immune system. The fact that there are no described cases of CRP deficiency in humans provides support that it may be critically important; however, the physiologic role of CRP is poorly understood. It is able to bind phosphocholine, thereby allowing recognition and removal of foreign pathogens that express this moiety, and also facilitates detection and clearance of phospholipid constituents of injured cells. It can also activate the classic complement pathway, stimulate cytokine production, and bind to receptors on phagocytic immune cells. These properties suggest that CRP is involved in the elimination of pathogens by closely interacting with the humoral and cellular immune systems. CRP is thought to have anti-inflammatory effects as well, but these are less completely understood.

ESR and CRP

2. How was CRP discovered? CRP was first described by Tillet and Francis in 1930,3 who recognized that serum from acutely infected patients with pneumococcal pneumonia contained a protein distinct from immunoglobulins that formed a precipitate when combined with the C polysaccharide fraction of Streptococcus pneumoniae. Moreover, they described that the degree of precipitation was strongest when the patient was acutely ill, and decreased as the patient recovered. These findings suggested that this CRP reflected an acute host response to inflammatory states and that this reaction could be used as a marker of disease activity. Subsequently, it was discovered that the increase in CRP was not unique to pneumococcal pneumonia but could be seen with other acute infections or inflammatory conditions,4 and contributed to the concept of the acute-phase response, which includes characteristic increases in concentration of acute-phase proteins such as CRP during inflammation. 3. What are the kinetics of CRP in response to inflammation? CRP levels in young healthy adults are usually less than 10 mg/L, but can increase as much as 10,000-fold in response to infection or inflammation.1 Serum CRP is produced by hepatocytes in response to cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor a (TNF-a) (Fig. 1). Transcriptional control of CRP synthesis is thought to be primarily due to IL-6, the main circulating physiologic mediator. CRP may also be produced by macrophages in atherosclerotic lesions, the kidney, alveoli, and the brain.5 After an acute injury, such as a major surgical procedure, serum CRP levels increase detectably starting at about 4 hours, peak in around 2 to 3 days, and decline with a plasma half-life of about 19 hours. Of importance, the plasma level of CRP is affected almost entirely by the synthesis rate, thus concentrations of CRP in the plasma directly reflect the degree and extent of tissue injury or inflammation. CRP levels fall quickly once the stimulus for synthesis ceases. These physiologic properties make CRP extremely useful for monitoring disease activity and response to therapy. 4. How is CRP measured? When initially assayed by a crude immunoprecipitation technique, measurement of CRP was time consuming and of limited acute clinical utility. Insensitive qualitative or semiquantitative techniques were mostly used, resulting in tests that were positive

Fig. 1. Mechanism of the acute phase. IL, interleukin; TNF, tumor necrosis factor.

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only in highly inflammatory conditions. At present, serum CRP levels can be accurately and quickly quantified by immunoassays that measure the amount of microprecipitates that form in a few seconds or minutes when antibodies to CRP are added to CRP-containing diluted serum. Typically the microprecipitates formed in the diluted serum are quantified by measuring the decrease in light passing through the serum (turbidimetry) or the amount of light scattered as light passes through the precipitate-containing serum (nephelometry). In North America, CRP concentrations may be reported in units of mg/dL or mg/L. The shift from reporting in mg/dL to reporting in mg/L spread with the development of more sensitive immunoassay techniques that allowed CRP to be measured well into the range of the normal population (for example, to a concentration of 1.0 mg/ L or below). These high-sensitivity CRP (hs-CRP) assays could then be used to measure variations in CRP concentrations within the normal population in the absence of overt clinical inflammation, and have been proposed as indicators of cardiac risk to supplement typical lipid and other risk factors for cardiovascular disease.6 Failure to recognize a 10-fold difference in CRP levels as reported by different laboratories using different units could be confusing, and could have important clinical consequences. 5. How much does it cost to run a CRP? The cost of measuring CRP in a clinical laboratory varies by laboratory; however, the current procedural terminology (CPT) code is 86140, which in 2011 was associated with a Medicare reimbursement of $7.28. 6. What are normal levels of CRP in healthy adults? For several years, the normal reference range of CRP in humans has been thought to be independent of age and sex. However, with the use of higher-sensitivity tests for CRP that allowed precise measurements within the normal range, it has been increasingly appreciated that age and sex influence the reference range. Using data generated from almost 9000 adults in the US National Health and Nutritional Examination Survey (1999–2002) revealed that median levels of CRP for all adults was 2.1 mg/L and that 90% of adults had levels of 10 mg/L or less.7 CRP levels were higher in women than in men and increased with age, presumably secondary to the increasing incidence of subclinical pathologies or normal variation. Based on a study of more than 22,000 individuals in the United States, one can roughly correct the CRP level for age by using the following formulas: upper limit of the reference range in mg/L equals age/5 for men and (age in years/5) 1 6 for women.8 A study of young healthy volunteer blood donors in the Netherlands demonstrated a median CRP concentration of 0.8 mg/L, but 90% had levels of 3.0 mg/L or less and 99% had levels 10 mg/L (1 mg/dL) or less.9 Thus, it is generally accepted that levels greater than 10 mg/L reflect clinically significant inflammatory disease in a young population, but higher values may be present in apparently healthy older populations. If hs-CRP is used for estimating cardiovascular risk, hs-CRP less than 1 mg/L is considered low risk, 1 to 3 mg/L average risk, and greater than 3 mg/ L high risk. If the CRP level is greater than 10 mg/L, guidelines6 indicate that CRP should not be used as a cardiac risk predictor, because inflammatory disease may be present. 7. What other factors influence normal levels of CRP in healthy individuals? The serum concentration of CRP in healthy individuals in part depends on genetic factors. Polymorphisms in proinflammatory cytokines and in the promoter region of

ESR and CRP

the CRP gene influence baseline levels, and can contribute to differences in CRP serum concentrations in healthy populations.10–13 8. What is the erythrocyte sedimentation rate? The erythrocyte sedimentation rate (ESR), or sed rate, is a laboratory test that measures the distance in millimeters that erythrocytes in a vertical tube settle under the influence of gravity in 1 hour (Fig. 2). It is a simple and inexpensive test that is an indirect measurement of serum acute-phase protein concentrations. The ESR depends on aggregation of red blood cells (RBCs) and rouleaux formation. The mechanism has been described in detail elsewhere.14–20 In brief, RBCs settle because the density of the cells is more than the density of plasma. As RBCs start to fall there is upward displacement by plasma, which opposes the initial downward movement, and little settling occurs. However, when erythrocytes aggregate (rouleaux formation) they settle more rapidly (higher ESR). Factors that lead to RBC aggregation and rouleaux formation include characteristics of the RBCs (ie, size, shape, and concentration) and charge-neutralizing characteristics of plasma proteins, which decrease the electrostatic repulsion of RBCs. Normally, aggregation and rouleaux formation of RBCs is impaired by the negative charge on the surface of erythrocytes. This repulsive electric field extends as far as the approximate diameter of 2 RBCs. For RBCs to aggregate, the repulsive electric field must be counteracted. Asymmetric, charged plasma proteins can counter the repulsive field of the erythrocytes. In general, the higher the molecular mass and more asymmetric the protein molecule, the more powerful the charge-neutralizing characteristics and the less the RBCs can repel each other. In acute inflammation, fibrinogen is the protein that makes the greatest

Fig. 2. Erythrocyte sedimentation rates.

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contribution to a rapid increase in ESR, because it is of high molecular weight, is asymmetric, and undergoes rapid increases to relatively high concentrations. In more chronic inflammatory states, immunoglobulins and other globulin proteins contribute significantly to an elevated ESR. Higher concentrations of large proteins increase plasma viscosity, which can decrease the ESR. These opposing effects of proteins contribute to the complexity of trying to predict the ESR based on isolated measurements of individual proteins. Anemia and RBC abnormalities also have significant effects on the ESR. In the presence of normal RBC morphology but reduced hematocrit, rouleaux formation is favored and the ESR will increase. Furthermore, the velocity of the upward flow of plasma is altered so that RBC aggregates will settle more quickly. Anemia aside, macrocytic RBCs fall more rapidly because of a higher surface-to-volume ratio, whereas microcytic cells settle more slowly. In sickle cell disease a low ESR is so common that an elevated ESR should raise concern for an occult infection. Numerous other factors may influence the ESR (Table 1). 9. How was ESR first discovered? Although differences in the properties of blood during acute illness have been recognized by physicians and healers for millennia, blood sedimentation was first studied systematically in 1894 by a Polish physician, Edmund Biernacki.21 He recognized that the blood sedimentation rate was different in different individuals and that fibrinogen levels played an important role in the ESR. In 1918, a Swedish hematologist, Robert Fahraeus, reported that the RBCs settled more rapidly in pregnant than nonpregnant women, and postulated that it might serve a role as a pregnancy test. Subsequently, a Swedish internist, Alf Westergren,22 described it as a test to monitor the inflammatory response and clinical progress of patients with tuberculosis. He also defined standards for the measurement of ESR. Since then, it has been used in clinical medicine as a nonspecific marker of systemic inflammation, making it one of the oldest laboratory tests still in use today. 10. How is ESR measured? The International Committee for Standardization in Hematology has designated the Westergren assay as the reference method.23,24 In the Westergren ESR method, anticoagulated blood is diluted, mixed, then placed in a vertical tube, and the distance (in millimeters) that the top of the layer of RBCs settles in 1 hour is measured, and reported in units of mm/h (see Fig. 2) The Wintrobe method for measurement of the ESR uses a different anticoagulant and a tube of different dimensions, and provides slightly different values.14 Many modifications of the ESR have been used to improve the test, for example, to minimize the effect of anemia, shorten the time to results, increase automation and efficiency, and lower the biosafety risk for technologists performing the test. At present, many ESR methods use variations of the Westergren method, with closed tubes to avoid risk of exposure to blood products. The zeta sedimentation rate (ZSR) uses controlled slow centrifugation steps in a specialized centrifuge, in an attempt to provide an equivalent of the ESR that minimizes the influence of hematocrit (anemia in particular) on the value measured. Several automated instruments, some including centrifugation steps, have been developed to increase the number of specimens that can be tested, and some automated instruments have shortened the test time to as little as 5 minutes. In large laboratories in the United

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Table 1 Factors that have been reported to influence the ESR Factor

Effect on Rate

Anemia

Increase

Mechanism Decreased RBC repulsion

Polycythemia

Decrease

Increased RBC repulsion, increased blood viscosity

Extreme leukocytosis

Decrease

Increased cell repulsion, increased blood viscosity

Disseminated intravascular coagulation

Decrease

Decreased fibrinogen

Increase Decrease Decrease Decrease Decrease Decrease

Related to ability to form rouleaux

Obesity

Increase

Inflammatory state (low grade)

Pregnancy

Increase

Inflammatory state (low grade)

Female gender

Increase

? Hormonal effects, lower hematocrit than males

Advanced age

Increase

? Variety of low-grade chronic inflammation

Increase Decrease Decrease Decrease

RBC membrane effects Unknown Anti-inflammatory Anti-inflammatory

Decrease

Effect of treatment, with decreased vascular volume

Renal failure

Increase

Anemia, hypoalbuminemia

Nephrotic syndrome

Increase

Hypoalbuminemia

Hypercholesterolemia

Increase

Effect on RBC membrane

Increase Increase Increase Decrease Decrease Decrease

Effect on zeta potential and RBC repulsion

Increase

Antierythrocyte antibodies cross-link RBCs leading to increased rouleaux formation

RBC abnormalities      

Macrocytosis Microcytosis Sickle cell disease Spherocytosis Acanthocytosis Anisopoikilocytosis

Drugs    

Heparin Valproic acid NSAIDs Steroids

Congestive heart failure

Protein abnormalities      

Elevated fibrinogens Elevated gammaglobulins Decreased albumin Hypofibrinogenemia Hypogammaglobulinemia Dysproteinemia with hyperviscosity state

Autoantibodies Cold agglutinins

(continued on next page)

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Table 1 (continued) Factor

Effect on Rate

Mechanism

Increase or decrease Increase

Laboratory factors

Technical factors  Dilutional problems  Increased temperature of specimen  Tilted ESR tube  Inadequate mixing  Clotting of blood sample  Short ESR tube  Vibration during testing

Increase Decrease Decrease Decrease Decrease

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; RBC, red blood cell. Data from Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J 1998;91(3):220–5; and Vennapusa B, De La Cruz L, Shah H, et al. Erythrocyte sedimentation rate (ESR) measured by the Streck ESR-Auto Plus is higher than with the Sediplast Westergren method: a validation study. Am J Clin Pathol 2011;135(3):386–90.

States, most ESR testing is performed by automated or semiautomatated versions of the test that are usually designed to be equivalent to the Westergren ESR, converted to mm/h. Correlations between the Westergren method and the alternatives are generally very good, but under some conditions and with some patient populations the alternative methods may not provide the same information as does the Westergren.25 Some methods yield results that are significantly higher than those of the Westergren method, particularly when the ESR is elevated.26 In light of the differences in ESR methods and general laboratory principles, the recommendation has been made that individual laboratories set or validate their normal reference range of ESR.27 11. How much does it cost to run an ESR? The cost of measuring ESR in a clinical laboratory varies by laboratory; however, the CPT code is 85652, associated with Medicare reimbursement of $3.80. 12. What factors influence the measurement of ESR? The major influence on the rate of sedimentation of erythrocytes suspended in plasma is the degree to which they aggregate with one another.14–16 Erythrocyte aggregation is affected by RBC membrane electric charges, plasma proteins that tend to counteract the cell surface charge, the concentration and shape of RBCs, and the frictional forces that surround the RBCs. Erythrocytes normally have negative charges that prevent cell aggregation (the zeta potential, the repulsive force characteristic of particles in suspensions), but any increase in asymmetric positively charged plasma proteins (ie, globulins, fibrinogen) will lead to erythrocyte aggregation or rouleaux formation. Albumin, the most plentiful plasma protein, has an inhibitory action on the ESR, such that in hypoalbuminemic inflammatory states the ESR may be more elevated than if the albumin was normal. Anemia tends to increase the ESR, because fewer RBCs are repelling each other, whereas polycythemia has the effect of lowering the ESR

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by increasing friction and increasing the concentration of erythrocytes repelling each other. In mathematical terms, these trends can be summarized as ESR being proportional to (fibrinogen 1 globulin proteins)/(albumin 1 hematocrit). Numerous other factors may influence the ESR (see Table 1). 13. What are normal rates of ESR in healthy adults? The generally accepted upper limit of normal for adults up to 50 years of age is an ESR of 15 mm/h in men and 20 mm/h in women. In apparently healthy older individuals, the ESR may be higher than in younger populations.28 A practical and commonly used formula for calculating the upper limit of older reference populations was proposed in 1983.17 Using this formula the maximum normal ESR rate in men equals age in years/2 and in women, (age in years 1 10)/2. This formula is simple, easy to use, and gives very good approximations of the upper limit of the reference range of ESR values for a given age and gender in adults. 14. How do ESR and CRP differ? Clinicians need to be aware a several important differences between the ESR and CRP (Table 2).16,29–31 1. The ESR is an indirect marker of serum acute-phase protein concentrations whereas CRP is a direct protein measurement, making it inherently more well-defined. 2. The ESR is affected by a multitude of compounding factors (see Table 2), particularly anemia and hypoalbuminemia caused by nutrition and protein-losing conditions such as nephrotic syndrome, which lead to misinterpretations in clinical practice, whereas CRP is affected only by the presence and degree of inflammation. 3. The reference range for the ESR is broad, particularly in elderly patients, in whom normal values have been as high as 40 to 50 mm/h (ie, 2 or 3 times the normal in

Table 2 Comparison of ESR and CRP ESR

CRP

Cost

Low

Low

Throughput time

5 minutes to 2 hours

Typically less than 30 minutes

Measurement

Indirect measure of proteins Corresponds primarily with fibrinogen levels in acute inflammation

Direct protein measurement Measures specific acute-phase protein

Rises

Days to weeks

Hours to days

Peak level

1–2 weeks

48 hours

Declines

Slowly (1–2 weeks)

Rapidly

Age and gender

Significant effect

Mild to moderate effect

Accuracy for inflammation

Frequent false positives

Rare false positives

Affected by multiple confounding factors (eg, RBC abnormalities)

Often

Never/rarely

Data from Johnson HL, Chiou CC, Cho CT. Applications of acute-phase reactants in infectious diseases. J Microbiol Immunol Infect 1999;32(2):73–82.

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young adults). The CRP is also affected by age and gender, but to a smaller degree (ie, older adult reference range upper limit only about twice young adult) than the ESR.8 4. As a patient’s condition worsens or improves, the ESR responds slowly, because fibrinogen, the major contributor to the short-term increase in ESR, has a half-life of days (depending on clotting status and other factors), and immunoglobulins (strongly contributing to the elevated ESR in chronic inflammatory states) have half-lives of weeks under normal physiologic states. This process can result in a significant lag between clinical changes and ESR values. CRP, on the other hand, rapidly rises in the presence of an inflammatory stimulus, peaks in about 48 hours, and returns to normal in as little as 3 to 7 days (Fig. 3) once the stimulus is removed. 5. A substantial number of ESR measurements are elevated by conditions other than inflammation, whereas this is extremely rare with CRP. False-positive ESRs could incur substantial costs and could place patients at risk for invasive procedures or other unnecessary treatments.31 15. What is the impact of normal pregnancy on ESR and CRP? Both ESR and CRP are elevated in normal pregnancy. However, the elevation of CRP is modest, with the upper limit typically only 15 mg/L until a woman is in labor, at which time it can increase further.32 Further elevation above those concentrations tends to be associated with amnionitis, preterm delivery, and neonatal problems.33 The ESR can increase dramatically during normal pregnancy. The upper limit of the reference range has been reported to be as high as 48 mm/h in the first half of pregnancy and up to 70 mm/h in the second half of pregnancy, with further elevations in anemic women.34

Fig. 3. Changes in CRP and ESR levels after stimulation.

ESR and CRP

APPROPRIATE USE

16. Can the ESR/CRP help to diagnose disease? ESR and CRP are both sensitive markers of inflammation and correlate with severity of inflammation, but they are not specific to any particular illness. These markers are more helpful in ruling out (ie, they have high negative predictive value), rather than ruling in any particular disease (ie, they have low positive predictive value).35 This is especially true when the pretest likelihood of a disease is low or moderate. For example, in giant cell arteritis (GCA), the sensitivity of the ESR is about 80% while the sensitivity of CRP is as high as 97.5%, and the combination (either positive) has a sensitivity of more than 99%.36 If the clinician’s pretest likelihood of GCA is low or moderate, a normal ESR or CRP makes the diagnosis extremely unlikely (<1%). On the other hand, if the pretest likelihood is high, even normal levels of inflammatory markers may not be enough to dissuade the clinician from prescribing empiric steroids and pursuing a temporal artery biopsy. When these tests are elevated in conditions such as GCA, they are helpful for following the course of disease and may contribute to determining the need for continued therapy. CRP is one of the most studied biomarkers of infection. It has been studied not only to distinguish infection from other inflammatory disorders, but to help differentiate among different types of infection. Modest elevations in CRP (10–100 mg/L) are usually representative of mild to moderate infections (viral or bacterial), connective tissue disorders, or malignancy.29 Levels above 100 mg/L are associated with a bacterial infection more than 80% of the time, but viral infections and autoimmune diseases can reach this level on occasion. There is no cutoff of CRP that can discriminate fungal from bacterial sepsis.2 For this reason, CRP levels alone can never be diagnostic of infection or a type of infection, as there is significant overlap of CRP levels with varying conditions. Its clinical utility is in ruling out rather than ruling in infection: an increased value does not automatically mean infection is present, but a normal level strongly argues against sepsis. Accordingly, the American Academy of Orthopedic Surgeons (AAOS)37 recommends checking an ESR and CRP in patients being evaluated for periprosthetic joint infections, noting that joint infection is very unlikely if both levels are normal, but the AAOS recommends a joint aspiration if either is abnormal. In a study of 370 serial internal medicine hospital admissions, an admission CRP value of greater than 200 mg/L was strongly associated with sepsis, whereas a CRP of less than 10 mg/L was never seen in sepsis.38 Moreover, evidence is mounting that the trend in CRP levels is more clinically useful than a single value.2 For instance, in the treatment of sepsis, an increasing CRP level suggests worsening infection, whereas a decreasing CRP implies adequacy of therapy.29 In this way CRP levels may be useful in helping to determine the duration of antibiotic therapy, as well as triaging when patients may be safe to leave the intensive care unit.39–41 Moreover, elevated concentrations of serum CRP levels on intensive care unit (ICU) admission correlate with an increased risk of organ failure and death. Persistently elevated CRP concentration levels are associated with poorer outcomes. Repeated measurements may be helpful in identifying those patients who require more aggressive interventions to prevent complications.42 17. What is the role of the ESR/CRP in determining disease activity or response to therapy? Perhaps the most clinically useful role of these biomarkers is in determining disease activity and response to therapy. Although these markers have limited utility in

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diagnosing different diseases, they can be extremely helpful in evaluating the severity of inflammation of a known disease and in assessing disease activity or response to therapy over time. The ESR and/or CRP tests are commonly used to monitor disease activity and response to therapy in temporal arteritis, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus (SLE), and invasive infections, such as osteomyelitis. Failure of these inflammatory markers to decline suggests worsening disease activity or inappropriate or inadequate therapy. ESR and CRP can serve as another parameter to help the clinician decide whether steroids should be tapered or discontinued in rheumatic diseases and whether antibiotics should be stopped, continued, or changed in infectious diseases. 18. What are some specific diseases or conditions whereby ESR/CRP have been shown to be helpful? The ESR and CRP have been shown to be clinically useful in the management of several disorders, including GCA, polymyalgia rheumatica, rheumatoid arthritis, SLE, infectious disease, and cardiovascular disease. 19. What is the role of ESR/CRP in giant cell arteritis and polymyalgia rheumatica? The diagnosis of polymyalgia rheumatica (PMR) and GCA are supported by elevated levels of ESR or CRP. Levels of ESR are commonly above 100 mm/h in GCA patients. However, neither test is 100% sensitive for either disorder. Studies strongly imply that a normal ESR can be seen in as many of 20% of patients with PMR43 and in 5% of patients with GCA.44 This finding is further confounded by the fact that apparently healthy older individuals may have ESR and CRP values that would be considered elevated when seen in younger populations. The newly proposed response criteria for PMR by the European League Against Rheumatism recommend use of CRP, rather than ESR, although either is acceptable.45 Of importance, patients with PMR who have normal ESR levels have the same frequency of positive temporal biopsy results as patients with elevated ESR values, although the former may have fewer systemic symptoms.46 Patients with GCA who have normal ESR levels are thought to have less severe systemic symptoms and decreased risk of visual loss,44 although some studies refute this.47 In addition to diagnosis and prognosis already described, the ESR and CRP are useful, if not totally reliable, surrogate markers for response to therapy. Persistently elevated levels of these inflammatory markers are associated with relapse or recurrence of disease.47,48 However, they are only to be used as part of the clinical assessment. For instance, clinicians should be reassured that the disease is controlled only if both the inflammatory marker is normal and there are no other clinical manifestations of disease. An abnormality of either of these raises the possibility for relapse or recurrence. Furthermore, if the degree of elevation of the inflammatory marker is extreme and out of proportion to the clinical manifestations, other sources of inflammation or infection should be investigated. 20. What is the role of ESR/CRP in rheumatoid arthritis? The main role of ESR and CRP in rheumatoid arthritis is to support early diagnosis in a patient with clinically suspected disease, and for disease monitoring and judging response to therapy. Elevation in either ESR or CRP can make small contributions to the diagnosis of rheumatoid arthritis, according to the current diagnostic criteria.49

ESR and CRP

In general, disease-modifying antirheumatic drug therapy lowers levels of these acutephase reactants, and this parallels inhibition of joint damage. However, decreases in these acute-phase reactants do not always correlate with lack of progression of disease, or vice versa. For instance, TNF inhibitors (ie, infliximab) have been shown to be joint protective even in the face of a persistently elevated CRP.50 Consequently, they are only part of the equation that the clinician needs to input when making decisions about therapy. In addition to monitoring, these acute-phase reactants are also useful for prognosticating severity of disease. Elevated levels are associated with early synovitis and erosions detected by magnetic resonance imaging,51 radiographic progression of disease,52 reduced bone mineral density,53 and long-term work disability.54 Of note, CRP levels in moderately active patients with rheumatoid arthritis are usually between 20 and 30 mg/L.55 In patients with extreme elevations (100 mg/L), infection would need to be in the differential diagnosis, especially if the patient appears well controlled otherwise. 21. What is the role of ESR/CRP in systemic lupus erythematosus? The degree of ESR elevation correlates with disease activity and accumulated tissue injury in SLE. However, CRP, normally an excellent marker of acute inflammation and disease activity, seems to have a muted response in lupus patients.56 It has been well described that even in patients with very active SLE, CRP levels are only modestly elevated. Sometimes even normal CRP levels are present during active disease. However, subsets of SLE patients can produce marked elevation of CRP (60 mg/ L), suggesting that lupus patients can mount a striking CRP response if the appropriate stimulus is encountered. Lupus serositis and infection are common causes of CRP levels of 60 mg/L and greater.57 Consequently, in a lupus patient without serositis, marked elevation of the CRP level is strongly suggestive of infection. 22. What is the role of ESR/CRP in infectious disease? The CRP, more so than the ESR, is helpful in identifying the presence of infectious disease, in determining prognosis, and in following response to therapy. For diagnosis, though nonspecific, the absolute level of CRP may be suggestive of the type of infection, but is it not accurate enough to discriminate among viral, bacterial, or fungal infections with any degree of certainty. In general, CRP levels of 100 mg/L or more are associated with a bacterial infection. In one study, CRP levels above 500 mg/L indicated an infection 88% of the time, and most were bacterial.58 In viral and fungal infections, CRP levels can occasionally reach concentrations higher than 100 mg/L, limiting CRP’s diagnostic usefulness. However, a CRP level of less than 10 mg/L would be very unlikely with any significant systemic bacterial infection. Others have suggested that CRP levels could distinguish between pneumonia and asthma and thus help decrease antibiotic use in hospitalized patients. In one study, a CRP level greater than 48 mg/L had a sensitivity of 91% and specificity of 93% for identifying patients with pneumonia.59 The investigators acknowledge that in using the cutoff of 48 mg/L, a small percentage of patients with pneumonia were not treated, but withholding antibiotics from those patients was not associated with adverse outcomes. In a meta-analysis looking at the diagnostic accuracy of systemic inflammatory markers in prosthetic joint infections, pooled sensitivity and specificity for CRP levels was 88% and 74%, respectively.60 Overall, the best data to date suggest that CRP levels alone are of limited usefulness for diagnostic purposes, but they can provide support for a clinical impression and alter the diagnostic probabilities until definitive diagnostic tests are available.

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Regarding prognosis, for patients with sepsis admitted to the ICU, those with CRP levels greater than 10 mg/L had higher complication and mortality rates when compared with those patients with CRP levels less than 10 mg/L.42 In this same study, patients with CRP levels greater than 100 mg/L had a significantly higher mortality (61%) if their CRP level increased after 48 hours compared with those in whom the CRP level decreased (15%). Several studies have also reported that high CRP levels at ICU discharge were associated with higher ICU readmission and post-ICU mortality rates.39–41 Perhaps the most important role for CRP is in judging response to therapy and in assisting with therapeutic guidance. In cases of osteomyelitis, infectious endocarditis, septic arthritis, and deep-seated tissue abscesses, consecutive CRP measurements may be used to observe progress or to alert the clinician to potential complications. A rapid decline in CRP levels supports a positive clinical response, whereas persistent or secondary CRP elevations imply inadequate therapy, noncompliance with therapy, or a complication. 23. What is the role of hs-CRP in cardiovascular disease? The use of CRP in cardiovascular disease is controversial. hs-CRP, which is commonly used in cardiovascular disease, is not different from regular, widely used CRP, but the “high-sensitivity” designation describes an assay that is able to measure low concentrations of CRP, well within the normal or reference range of CRP in the generally healthy population. CRP levels have been shown to be an independent risk factor, and have prognostic value in both ischemic stroke61 and acute coronary syndromes.62,63 However, it is not clear how much incremental value it provides above traditional risk factors or prognostic elements. For instance, its true ability to predict 30-day mortality after an acute myocardial infarction, above and beyond that of prognostic factors such as the creatinine kinase peak, electrocardiogram, and cardiac ejection fraction, is unclear.64 The same can be said for use of CRP in acute ischemic stroke, namely that CRP concentrations are predictive of future cardiovascular events, but whether adding CRP levels to time-honored prognostic factors should change management is unknown.5 Furthermore, no high-quality studies have shown that interventions aimed at lowering CRP levels reduce the risk of subsequent cardiovascular disease. Consequently, the authors believe that the therapeutic implication of elevated CRP concentrations in acute cardiac syndrome or acute ischemic stroke is of limited clinical utility. These clinical scenarios require clinicians to aggressively pursue established secondary preventive strategies, whether the CRP levels are elevated or not. Studies show that evidence-based secondary prevention strategies are consistently underutilized.65 The role of hs-CRP in primary prevention is also controversial, and many of the issues concerning its use as a risk factor have been reviewed.66 One caveat regarding use of CRP is that the within-subject CRP standard deviation is 1.2 mg/L, so that a patient with a CRP concentration of 2 mg/L (a moderate risk category by some classifications) could have a level of 0.8 to 3.2 mg/L on remeasurement, placing the patient in either a low or high risk category. Because CRP measurements during acute hospitalizations are likely to reflect the added influence of the underlying problem leading to acute hospitalization, with additional causes for variations, the authors would recommend not checking or using CRP during acute hospitalization as a cardiac risk factor. 24. Which is the preferred inflammatory biomarker to order, ESR or CRP? ESR and CRP levels are the most widely used tests to monitor and detect inflammatory disorders. The tests are often ordered in tandem, but there is little evidence to

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support the clinical utility of this common practice in most clinical situations. When infection is being considered and inflammatory markers are to be used to help in the diagnostic considerations or to monitor the course, the CRP test is almost always preferred, and is the only test that should be performed. A recent study retrospectively evaluated all concomitant ESR and CRP measurements that were performed during 1 year to examine their level of agreement and diagnostic accuracy.31 Among nearly 6000 hospitalized patients in France, 67% had concordant ESR and CRP results (both normal or both elevated). In patients with discordant results, the most common discordance (85%) was elevated ESR but normal CRP. Review of 99 randomly selected charts with discordant results revealed that all 25 patients with elevated CRP but normal ESR had active inflammatory disease (ie, had false-negative ESR results); by contrast, in the 74 patients with elevated ESR but normal CRP, only 6 had active inflammatory disease (ie, had false-negative CRP results). A substantial number of ESR measurements were false positives, whereas CRP measurement yielded no false positives and has been shown to have a very high negative predictive value for active inflammation. Most studies comparing ESR with CRP have yielded similar results, but in some, the ESR is reported to perform better than the CRP level. In a study of 2000 outpatients with ESR and CRP performed on the same day, 87 (4.2%) were classified as having major discordant results, with 55 in the high ESR/low CRP group, and 32 in the high CRP/low ESR group.67 In this series, the discordant patients with high ESR/normal CRP had a high association with infection and azotemia. There are many differences between the 2 studies cited, including that the second study, in which discordant results seemed to favor the performance of the ESR result, included only outpatients,67 whereas the first study, clearly demonstrating greater utility for CRP, was an inpatient study.31 Overall, the best evidence to date strongly supports CRP as being the more accurate acute inflammatory marker when compared with the ESR for inpatients and acute inflammatory conditions, whereas the ESR may be valuable in following patients with chronic inflammation.68,69 It is the opinion of the authors that CRP be the preferred inflammatory marker ordered in patients in the acute hospital setting for evaluating and monitoring infection. In the evaluation of patients with lupus or suspected GCA, the ESR may provide additional information. Furthermore, if the CRP measurement does not fit the clinical picture, then ordering other inflammatory marker tests may sometimes help clarify otherwise confusing clinical situations. For example, extreme elevation (>500 mg/dL) of serum ferritin is particularly useful as a marker of inflammation in evaluating patients with hemophagocytic syndrome or with systemic-onset juvenile idiopathic arthritis (Still disease) in adults or children. 25. Are there circumstances whereby one should considering ordering both ESR and CRP? There are a few circumstances whereby clinicians may want to consider ordering an ESR in addition to the CRP. When GCA is suspected, with an expectation of starting corticosteroids, baseline ESR and CRP are both recommended to improve diagnostic sensitivity and to establish baselines for future comparison. In other rheumatic or primary inflammatory conditions, establishing a baseline value of both inflammatory markers before starting therapy may be helpful in allowing future comparisons. Another such condition is in managing patients with SLE. Although CRP is an excellent marker of acute inflammation and disease activity, its muted response in SLE seems to be an exception.56 It has been well described that even in patients with very active

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SLE, CRP levels are only modestly elevated. Occasionally even normal CRP levels have been described. However, subsets of SLE patients can produce marked elevation of CRP (60 mg/L), suggesting that lupus patients can mount a striking CRP response if the appropriate stimulus is encountered. Lupus serositis and infection are common causes of CRP levels of 60 mg/L and higher.57 Furthermore, in a lupus patient without serositis, marked elevation of the CRP level is suggestive of infection. By contrast, the ESR correlates well with disease activity and may be quite elevated, even in the absence of infection or serositis. The mechanism of the muted CRP response in lupus remains unclear. One hypothesis is that genetically determined low levels of CRP may be a risk factor for SLE.70 Low CRP levels may contribute to defective clearance of autoantigens, resulting in increased immunogenicity. Another hypothesis is that lupus patients have amplified expression of interferon (IFN)-regulated genes leading to an increase in the production of IFN, which may inhibit CRP synthesis.71 Support for the latter possibility comes from knowledge that other diseases (ie, polymyositis, dermatomyositis, and primary Sjo¨gren) associated with IFN gene expression are also associated with relatively low levels of CRP.56 Consequently, in the appropriate clinical scenario, one might consider ordering an ESR in addition to a CRP in patients with SLE. For unknown reasons, CRP elevation also seems to be blunted in ulcerative colitis, leukemia, and graft-versushost disease,1 suggesting that ESR and other markers may be better measures of disease activity. 26. What are the diagnostic considerations and approaches when there is an unexplained elevation in ESR and/or CRP? The ESR should not be used as a screening test for disease, but what is one to do when faced with a patient with an unexplained elevated ESR? Some clinicians are overly concerned with modestly elevated ESRs (30–50 mm/h) in asymptomatic patients, but they need not be, because modest elevations of the ESR lack sensitivity, specificity, and have poor predictive value. Often the test need not have been ordered in the first place, and should serve as a reminder to not order unnecessary tests. Studies confirm, reassuringly, that most of these patients do not have serious abnormalities. Furthermore, in the vast majority of patients the elevated ESR returned to normal on subsequent evaluation. Therefore, in asymptomatic patients with a modest elevation of the ESR, physicians should resist the urge to search for etiological factors.15 A good history, physical examination, routine health screening, and perhaps a few simple blood tests (complete blood count, chemistry) are all that is warranted. If the total protein is also elevated, then a serum protein electrophoresis may be useful to evaluate for a monoclonal gammopathy. In most patients, the elevated ESR will be transient. However, among patients with extreme elevations of the ESR (100 mm/h), most (in the range of 95%) have a significant identifiable cause: malignancy (typically metastatic), infection, or connective tissue disease.14,15,72 Renal disease with proteinuria is also prominent in some studies. An age-appropriate and thoughtful evaluation focusing on malignancy, infection, and connective tissue disease is recommended in this setting. A suggested evaluation is outlined (Box 1). Almost all healthy young adults will have CRP levels of less than 10 mg/L.9 Moderate increases in CRP (10–100 mg/L) are usually representative of mild to moderate infections (viral or bacterial), connective tissue disorders, or malignancy. Levels above 100 mg/L strongly point to a bacterial infection more than 80% of the time, but it must be noted that viral infections can reach this level on occasion.4,29 Systemic vasculitis, major trauma, inflammatory bowel disease, and adult Still disease or other autoinflammatory

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Box 1 Proposed evaluation of patient with persistent unexpected markedly elevated ESR (eg, ESR ‡100 mm/h)  Thorough history and physical examination (note potential abscesses, arthritis, heart murmur, and so forth)  Complete blood count with differential and platelet count  Basic metabolic profile (electrolytes, blood urea nitrogen, creatinine)  Liver function tests  Urinalysis  Purified protein derivative or interferon-g release assay  Human immunodeficiency virus test  Antinuclear antibody  Serum protein electrophoresis, serum-free light chains  Chest radiograph  Blood cultures including acid-fast bacillus and fungal cultures if indicated  C-reactive protein  Age-appropriate cancer screening Data from Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med 1985;78(6 Pt 1):1001–9.

disease would also need to be considered when CRP levels are above 100 mg/L in the right clinical setting. In one study, serious (primarily bacterial) infections accounted for 88% of episodes in which the CRP level was greater than 500 mg/L.58 In contrast to extreme elevations of the ESR, extreme elevations of CRP are associated with bacterial infection. 27. Is there any clinical utility to evaluating a low ESR? There are numerous factors that can decrease the ESR (see Table 1), some of the more commonly associated ones being RBC changes or plasma protein abnormalities. RBCs with anisopoikilocytosis, as in severe iron deficiency anemia, hemoglobinopathies (ie, sickle cell disease), spherocytosis, and acanthocytosis thwart rouleaux formation and are associated with low ESRs. Therefore, an increased ESR in a patient with sickle cell disease is suggestive of infection.14 Other entities associated with very low ESRs are polycythemia vera, hypofibrinogenemia, or afibrinogenemia. In one study looking at 358 patients with an ESR of 1 mm/h, 38% of patients had no evidence of disease and 94% had no diseases ordinarily associated with a low ESR.73 Thus, it seems that an extremely low ESR is of no diagnostic or clinical value. However, if one encounters an ESR of 0 to 1 mm/h, it seems reasonable to check a complete blood count, as this could suggest polycythemia, severe microcytosis, or a hemoglobinopathy. Furthermore, although monoclonal gammopathies typically lead to increased rouleaux formation and an elevated ESR, the complication of hyperviscosity syndrome may be entertained in patients with hyperproteinemia associated with monoclonal gammopathies (ie, multiple myeloma) and an ESR that is very low.

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TEST LIMITATIONS

28. What are common pitfalls to avoid with the use of these biomarkers? Perhaps the most common pitfall with the use of these markers of inflammation is the overreliance placed on them by some clinicians. These markers are best used as an adjunct to clarify a history and physical examination, and to help monitor an established diagnosis. Taken alone, they are of very little diagnostic utility. Overreliance on laboratory tests may lead to a false reassurance when they are normal, or inappropriate testing and treatment if they are elevated. The significant risks and costs of such action must also be taken into account. It is the opinion of the authors that clinicians should use CRP, rather than the ESR, as the preferred acute inflammatory biomarker for hospitalized patients. The CRP is the more accurate and better standardized measure of acute inflammation, and rarely leads to false-positive results.31 Moreover, CRP is not affected by the multitude of confounders that affect the ESR (see Table 1). CRP is principally only affected by the presence and degree of inflammation. There are a couple of important caveats regarding CRP. In those presenting with septic shock and fulminant hepatic failure, CRP levels may be markedly decreased.74 This decrease may occur because circulating CRP is produced almost exclusively by the liver, and its production may be drastically impaired because of the extensive loss of hepatic synthetic function. Whether CRP concentrations are good markers of infection in patients with less severe liver disease, such as cirrhosis, is unclear because results have been conflicting.75,76 It may be that CRP levels correlate with the degree of hepatic synthetic dysfunction and that the worse the liver damage, the more that CRP synthesis is impaired. It has also been reported that CRP serum levels rarely can be misleadingly low in the setting of massive proteinuria (>8 g per day), because of clearance of CRP into the urine.77 Although small amounts of CRP may deposit in the kidney in the setting of inflammatory renal disease, and small amounts of CRP may be excreted in the urine, significant depression of CRP resulting from these mechanisms is rare.

PRACTICE IMPROVEMENT

29. How can hospital systems promote appropriate use of these biomarkers? Inappropriate use of laboratory tests is commonplace, wasteful, associated with the increased need for RBC transfusions in hospitalized patients, and may expose patients to unnecessary diagnostic tests and treatments.78 Regarding the use of CRP and ESR tests, the authors opine that hospital systems should educate their providers on the preference for ordering CRP instead of the ESR as the general inflammatory marker of choice, and use information technology systems to promote appropriate testing. 30. Are there ways to improve coordination between inpatient (acute disease) and outpatient (chronic disease) follow-up ordering of inflammatory markers? The growth of hospital medicine has exploded during the past decade,79 in part because hospitalist care is associated with shorter lengths of stays and lower hospital costs. However, this new model of health care delivery may lead to increased fragmentation of care.80 Discontinuity between hospitalists and primary care providers

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(PCPs) might cause miscommunication, and emphasizes the need for hospitalists to coordinate patient management across the care continuum by engaging PCPs during patient follow-up. In relation to the use of ESR and CRP, it is important that hospitalists and PCPs understand that levels of acute-phase reactants obtained during the acute setting (eg, myocardial infarction, lupus flare, infectious process) cannot be used for the purpose of long-term cardiovascular risk assessment. For instance, PCPs must wait until after the acute process has resolved and acute-phase proteins have returned to baseline before measuring hs-CRP levels for long-term cardiovascular risk assessment. Failure to do so will overestimate one’s individual risk. Furthermore, it may be helpful for the PCP to be aware of which inflammatory marker was followed in the hospital if out-of-hospital serial measurements are also obtained, so that appropriate comparisons can be made. GUIDELINES AND STATEMENTS

31. What guidelines include measurement of CRP or ESR? Sox HC Jr, Liang MH. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med 1986;104(4):515–23. Jou JM, Lewis SM, Briggs C, et al. ICSH review of the measurement of the erythrocyte sedimentation rate. Int J Lab Hematol 2011;33(2):125–32. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107(3):499–511. Napoli M, Schwaninger M, Cappelli R, et al. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke 2005;36(6):1316–29. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:1–38. Greenland P, Alpert JS. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. A report of the American Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56(25):e50–103. Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: clinical characteristics and use of biochemical markers in acute coronary syndromes. Circulation 2007;115(13):e356–75. Myers GL, editor. Emerging biomarkers for primary prevention of cardiovascular disease and stroke. Washington, DC: National Academy of Clinical Biochemistry; 2009. p. 70. National Collaborating Centre for Chronic Conditions. Rheumatoid arthritis: the management of rheumatoid arthritis in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2009. (NICE clinical guideline; no. 79). Institute for Clinical Systems Improvement (ICSI). Diagnosis and treatment of chest pain and acute coronary syndrome (ACS). Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2010. p. 72. AGA Institute on “Management of Acute Pancreatitis” Clinical Practice and Economics Committee, AGA Institute Governing Board. AGA Institute medical position statement on acute pancreatitis. Gastroenterology 2007;132(5):2019–21.

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American Academy of Orthopedic Surgeons (AAOS). The diagnosis of periprosthetic joint infections of the hip and knee. Rosemont (IL): American Academy of Orthopedic Surgeons (AAOS); 2010. p. 286. FUTURE DIRECTIONS

32. What would an ideal test of inflammation look like? An ideal clinical test of inflammation would be sensitive and responsive to all inflammatory states, but be able to signal (by magnitude of response or other indicator) what category and severity of inflammation is occurring. The ideal panel would be able to distinguish inflammation across the etiological spectrum: infection versus trauma versus malignancy versus autoimmunity versus alloimmunity versus autoinflammatory triggers. It is possible that a panel of markers would be able to fulfill such a role. As basic science studies of inflammation and the innate immune system progress, additional candidate biomarkers will undoubtedly be tested. For example, a report recently claims that measurement of the protein pentraxin-3, highly homologous to CRP, may be a useful marker for vasculitis, acute coronary syndromes, preeclampsia, and others.81 There is potential for cytokine measurements to be used clinically, and it has been suggested that measurement of IL-6 may be a somewhat better indicator of septic prosthetic hips than CRP, which is superior to ESR.60 Most cytokines are present in plasma at very low concentrations, and many are unstable during routine specimen handling, so they may be problematic. In some instances, rather than measuring the cytokine itself, a cytokine signature may be measured, consisting of characteristic downstream changes in concentrations of a panel of proteins or peptides. The IFN signature panel is being explored as a disease activity marker for SLE and related autoimmune rheumatic diseases. Other panels are being explored as measures of disease activity and inflammation for a variety of diseases. Individual inflammatory markers may have improved the predictive or diagnostic value for particular circumstances or diagnoses. The inflammatory biomarker procalcitonin has been demonstrated to be a reasonably effective marker of bacterial infection, a topic reviewed elsewhere in this issue. The iron-binding protein ferritin is another acute-phase protein. Modest elevations in the absence of inflammation are characteristic of hemochromatosis. For reasons that are still obscure, extreme elevations, including concentrations greater than 100,000 mg/dL, can be seen in patients with hemophagocytosis (also known as hemophagocytic lymphohistiocytis), and in childhood and adult patients with Still disease, as well as in massive hepatic necrosis. The ability to measure nucleic acids more efficiently and inexpensively will undoubtedly influence detection of inflammation. Genetics, as already mentioned, influence baseline levels of protein markers, and ready access to such genetic information may be available. Direct measurement of RNA, either messenger RNA encoding for biomarkers or small, so-called microRNAs that are present in the circulation and seem to have a regulatory role, may be clinically useful. REFERENCES

1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111(12):1805–12. 2. Vincent JL, Donadello K, Schmit X. Biomarkers in the critically ill patient: C-reactive protein. Crit Care Clin 2011;27(2):241–51.

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3. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930;52(4):561–71. 4. Clyne B, Olshaker JS. The C-reactive protein. J Emerg Med 1999;17(6):1019–25. 5. Di Napoli M, Schwaninger M, Cappelli R, et al. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke 2005;36(6):1316–29. 6. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107(3):499–511. 7. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Engl J Med 2005;352(15):1611–3. 8. Wener MH, Daum PR, McQuillan GM. The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration. J Rheumatol 2000;27(10):2351–9. 9. Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for human Creactive protein. Clin Chim Acta 1981;117(1):13–23. 10. Carlson CS, Aldred SF, Lee PK, et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 2005;77(1):64–77. 11. Crawford DC, Sanders CL, Qin X, et al. Genetic variation is associated with Creactive protein levels in the third national health and nutrition examination survey. Circulation 2006;114(23):2458–65. 12. Kathiresan S, Larson MG, Vasan RS, et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 2006;113(11):1415–23. 13. Reiner AP, Wurfel MM, Lange LA, et al. Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation. Arterioscler Thromb Vasc Biol 2008;28(7):1407–12. 14. Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med 1985;78(6 Pt 1):1001–9. 15. Sox HC Jr, Liang MH. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med 1986;104(4):515–23. 16. Jurado RL. Why shouldn’t we determine the erythrocyte sedimentation rate? Clin Infect Dis 2001;33(4):548–9. 17. Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983;286(6361):266. 18. Brigden M. The erythrocyte sedimentation rate. still a helpful test when used judiciously. Postgrad Med 1998;103(5):257–62, 272–4. 19. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J 1998;91(3):220–5. 20. Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999;60(5):1443–50. 21. Grzybowski A, Sak JJ. Who discovered the erythrocyte sedimentation rate? J Rheumatol 2011;38(7):1521–2 [author reply: 1523]. 22. Westergren A. Studies of the suspension stability of blood in pulmonary tuberculosis. Acta Med Scand 1921;54:247–82. 23. ICSH recommendations for measurement of erythrocyte sedimentation rate. International Council for Standardization in Haematology (expert panel on blood rheology). J Clin Pathol 1993;46(3):198–203.

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24. Jou JM, Lewis SM, Briggs C, et al. ICSH review of the measurement of the erythocyte sedimentation rate. Int J Lab Hematol 2011;33(2):125–32. 25. Hardeman MR, Levitus M, Pelliccia A, et al. Test 1 analyser for determination of ESR. 1. practical evaluation and comparison with the Westergren technique. Scand J Clin Lab Invest 2010;70(1):21–5. 26. Vennapusa B, De La Cruz L, Shah H, et al. Erythrocyte sedimentation rate (ESR) measured by the Streck ESR-Auto Plus is higher than with the Sediplast Westergren method: a validation study. Am J Clin Pathol 2011;135(3): 386–90. 27. NCCLS. Report No.: H2-A4. 4th edition. Reference and selected procedure for the erythrocyte sedimentation rate (ESR) test; approved standard, vol. 20. Wayne (PA): NCCLS/Clinical and Laboratory Standards Institute; 2000. p. 27. 28. Bottiger LE, Svedberg CA. Normal erythrocyte sedimentation rate and age. Br Med J 1967;2(5544):85–7. 29. Johnson HL, Chiou CC, Cho CT. Applications of acute phase reactants in infectious diseases. J Microbiol Immunol Infect 1999;32(2):73–82. 30. Osei-Bimpong A, Meek JH, Lewis SM. ESR or CRP? A comparison of their clinical utility. Hematology 2007;12(4):353–7. 31. Colombet I, Pouchot J, Kronz V, et al. Agreement between erythrocyte sedimentation rate and C-reactive protein in hospital practice. Am J Med 2010;123(9): 863.e7–863.e13. 32. Watts DH, Krohn MA, Wener MH, et al. C-reactive protein in normal pregnancy. Obstet Gynecol 1991;77(2):176–80. 33. Watts DH, Krohn MA, Hillier SL, et al. Characteristics of women in preterm labor associated with elevated C-reactive protein levels. Obstet Gynecol 1993;82(4 Pt 1): 509–14. 34. van den Broe NR, Letsky EA. Pregnancy and the erythrocyte sedimentation rate. BJOG 2001;108(11):1164–7. 35. Gerlach H, Toussaint S. Sensitive, specific, predictive. statistical basics: how to use biomarkers. Crit Care Clin 2011;27(2):215–27. 36. Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis. Ophthalmology 2006;113(10):1842–5. 37. American Academy of Orthopaedic Surgeons (AAOS). The diagnosis of periprosthetic joint infection of the hip and knee. American Academy of Orthopaedic Surgeons (AAOS); 2010. p. 286. Available at: http://www.aaos.org/research/ guidelines/PJIguideline.pdf. Accessed February 20, 2012. 38. Keshet R, Boursi B, Maoz R, et al. Diagnostic and prognostic significance of serum C-reactive protein levels in patients admitted to the department of medicine. Am J Med Sci 2009;337(4):248–55. 39. Ho KM, Dobb GJ, Lee KY, et al. C-reactive protein concentration as a predictor of intensive care unit readmission: a nested case-control study. J Crit Care 2006; 21(3):259–65. 40. Ho KM, Lee KY, Dobb GJ, et al. C-reactive protein concentration as a predictor of in-hospital mortality after ICU discharge: a prospective cohort study. Intensive Care Med 2008;34(3):481–7. 41. Grander W, Dunser M, Stollenwerk B, et al. C-reactive protein levels and post-ICU mortality in nonsurgical intensive care patients. Chest 2010;138(4): 856–62. 42. Lobo SM, Lobo FR, Bota DP, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003;123(6):2043–9.

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43. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al. Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. A more benign syndrome. Arch Intern Med 1997;157(3):317–20. 44. Salvarani C, Hunder GG. Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurrence in a population-based study. Arthritis Rheum 2001;45(2):140–5. 45. Leeb BF, Bird HA, Nesher G, et al. EULAR response criteria for polymyalgia rheumatica: results of an initiative of the European Collaborating Polymyalgia Rheumatica Group (subcommittee of ESCISIT). Ann Rheum Dis 2003;62(12): 1189–94. 46. Proven A, Gabriel SE, O’Fallon WM, et al. Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 1999;26(6):1333–7. 47. Salvarani C, Cimino L, Macchioni P, et al. Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum 2005; 53(2):293–7. 48. Cantini F, Salvarani C, Olivieri I, et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis Rheum 2000;30(1):17–24. 49. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62(9):2569–81. 50. Smolen JS, Van Der Heijde DM, St Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006;54(3):702–10. 51. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998;57(6):350–6. 52. Graudal N, Tarp U, Jurik AG, et al. Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender joints, the erythrocyte sedimentation rate, and hemoglobin: longterm course and association to radiographic progression. J Rheumatol 2000;27(1):47–57. 53. Gough A, Sambrook P, Devlin J, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 1998;25(7):1282–9. 54. Wolfe F, Hawley DJ. The longterm outcomes of rheumatoid arthritis: work disability: a prospective 18 year study of 823 patients. J Rheumatol 1998;25(11): 2108–17. 55. Aletaha D, Smolen JS. The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses. Rheumatology (Oxford) 2002; 41(12):1367–74. 56. Gaitonde S, Samols D, Kushner I. C-reactive protein and systemic lupus erythematosus. Arthritis Rheum 2008;59(12):1814–20. 57. Becker GJ, Waldburger M, Hughes GR, et al. Value of serum C-reactive protein measurement in the investigation of fever in systemic lupus erythematosus. Ann Rheum Dis 1980;39(1):50–2. 58. Vanderschueren S, Deeren D, Knockaert DC, et al. Extremely elevated C-reactive protein. Eur J Intern Med 2006;17(6):430–3. 59. Bafadhel M, Clark TW, Reid C, et al. Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD. Chest 2011;139(6):1410–8.

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60. Berbari E, Mabry T, Tsaras G, et al. Inflammatory blood laboratory levels as markers of prosthetic joint infection: a systematic review, and meta-analysis. J Bone Joint Surg Am 2010;92(11):2102–9. 61. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001;32(4):917–24. 62. Correia LC, Lima JC, Rocha MS, et al. Does high-sensitivity C-reactive protein add prognostic value to the TIMI-risk score in individuals with non-ST elevation acute coronary syndromes? Clin Chim Acta 2007;375(1–2):124–8. 63. He LP, Tang XY, Ling WH, et al. Early C-reactive protein in the prediction of longterm outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010;96(5):339–46. 64. Zebrack JS, Anderson JL. Should C-reactive protein be measured routinely during acute myocardial infarction? Am J Med 2003;115(9):735–7. 65. Spertus JA, Radford MJ, Every NR, et al. Challenges and opportunities in quantifying the quality of care for acute myocardial infarction: summary from the acute myocardial infarction working group of the American Heart Association/American College of Cardiology first scientific forum on quality of care and outcomes research in cardiovascular disease and stroke. J Am Coll Cardiol 2003;41(9):1653–63. 66. McCormack JP, Allan GM. Measuring hsCRP—an important part of a comprehensive risk profile or a clinically redundant practice? PLoS Med 2010;7(2): e1000196. 67. Costenbader KH, Chibnik LB, Schur PH. Discordance between erythrocyte sedimentation rate and C-reactive protein measurements: clinical significance. Clin Exp Rheumatol 2007;25(5):746–9. 68. Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. J Rheumatol 1997;24(8):1477–85. 69. Ward MM. Relative sensitivity to change of the erythrocyte sedimentation rate and serum C-reactive protein concentration in rheumatoid arthritis. J Rheumatol 2004; 31(5):884–95. 70. Edberg JC, Wu J, Langefeld CD, et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum Mol Genet 2008;17(8): 1147–55. 71. Enocsson H, Sjowall C, Skogh T, et al. Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares? Arthritis Rheum 2009;60(12):3755–60. 72. Fincher RM, Page MI. Clinical significance of extreme elevation of the erythrocyte sedimentation rate. Arch Intern Med 1986;146(8):1581–3. 73. Zacharski LR, Kyle RA. Low erythrocyte sedimentation rate: clinical significance in 358 cases. Am J Med Sci 1965;250:208–11. 74. Silvestre JP, Coelho LM, Povoa PM. Impact of fulminant hepatic failure in C-reactive protein? J Crit Care 2010;25(4):657.e7–657.e12. 75. Le Moine O, Deviere J, Devaster JM, et al. Interleukin-6: an early marker of bacterial infection in decompensated cirrhosis. J Hepatol 1994;20(6):819–24. 76. Bota DP, Van Nuffelen M, Zakariah AN, et al. Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med 2005;146(6):347–51. 77. Laiho K, Tiitinen S, Teppo AM, et al. Serum C-reactive protein is rarely lost into urine in patients with secondary amyloidosis and proteinuria. Clin Rheumatol 1998;17(3):234–5. 78. Cosimi AB. Modern day bloodletting: is that laboratory test necessary? Arch Surg 2011;146(5):527.

ESR and CRP

79. Kuo YF, Sharma G, Freeman JL, et al. Growth in the care of older patients by hospitalists in the United States. N Engl J Med 2009;360(11):1102–12. 80. Kuo YF, Goodwin JS. Association of hospitalist care with medical utilization after discharge: evidence of cost shift from a cohort study. Ann Intern Med 2011; 155(3):152–9. 81. Mantovani A, Garlanda C, Doni A, et al. Pentraxins in innate immunity: from Creactive protein to the long pentraxin PTX3. J Clin Immunol 2008;28(1):1–13.

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