C-reactive protein (CRP) Clinical guide C-reactive protein (CRP) is a sensitive marker of inflammation. As such it has for a long time been used to di

Transcription

1 C-reactive protein Clinical guide CRP ISO91 CERTIFIED Orion Diagnostica Oy P.O.Box 83, FI-211 Espoo, Finland Telephone Telefax E, Erweko 7/26

2 C-reactive protein (CRP) Clinical guide C-reactive protein (CRP) is a sensitive marker of inflammation. As such it has for a long time been used to distinguish bacterial infections from viral infections, assess the severity of tissue damage and monitor antibiotic treatment. Recently CRP has also been shown to be useful in predicting the risk of cardiovascular events. The purpose of this guide is to provide an overview of CRP, its diagnostic potential and its value in clinical practice. While not exhaustive in its coverage, the guide highlights some of the areas where CRP measurement can assist the clinician in making pertinent decisions about treatment. Introduction... 4 C-reactive protein (CRP)...6 CRP versus erythrocyte sedimentation rate (ESR) 8 CRP versus white blood cell count (WBC)... 1 CRP in comparison with other acute-phase proteins (SAA, IL-6, procalcitonin)..11 Bacterial versus viral infections...13 CRP in monitoring antibiotic therapy CRP in various clinical settings Severe infections such as septicaemia, endocarditis and osteomyelitis...18 Meningitis...19 Pneumonia and bronchitis...2 Sinusitis and bacterial pharyngitis (sore throat)...21 Urinary tract infections...22 Pelvic inflammatory disease (PID) Rheumatoid arthritis and systemic lupus erythaematosus (SLE)...23 CRP in myocardial infarction...25 Surgery and postoperative infections, trauma Tissue injury Preoperative and postoperative infections...27 Transplantation Appendicitis CRP in point-of-care testing...3 Ultrasensitive CRP Orion Diagnostica s CRP assays... 34

3 Introduction C-reactive protein (CRP) is an acute-phase protein normally present in very low concentrations in the serum of healthy people. During the inflammatory process of bacterial infections, in connection with tissue injury and after surgery, CRP concentrations are markedly increased. Elevated concentrations of CRP can be detected within 6-12 h after the onset of the inflammatory process. As CRP is usually elevated in bacterial infections but not in viral infections, it can be used as a basic tool for distinguishing bacterial infections from viral ones. CRP concentrations in serum increase and decrease faster than erythrocyte sedimentation rate (ESR) in response to changes in the patient's condition. If the patient recovers uneventfully, serum CRP will usually return to values under 1 mg/l within a few days. ESR, on the other hand, exhibits extremely wide variation, and normal values are usually reached only after a longer period. Since CRP concentrations drop rapidly, at roughly 5% a day, CRP is useful in monitoring the efficacy of antibiotic treatment. A downward trend in CRP concentrations indicates that treatment is progressing well, and treatment can often be stopped when the CRP value reaches the normal range. CRP is not only a marker of severe infection and trauma but can also be used to predict a risk of developing cardiovascular disease. Even minimally increased CRP values (2-3 mg/l) double the risk of future atherothrombotic events, compared with CRP values of approx. 1 mg/l. CRP is useful, for example, in distinguishing bacterial infections from viral infections monitoring the course of an illness monitoring and controlling postoperative infections following up the efficacy of antimicrobial therapy predicting future cardiovascular diseases. 4 5

4 C-reactive protein (CRP) CRP is a cyclic pentameric serum protein with a relative molecular mass of approximately 12 kd (Fig. 1). It has five identical noncovalently bound subunits each composed of 26 amino acids. It is synthesised in the liver and epithelial cells upon stimulation by inflammatory lymphokines (interleukin-6, interleukin-1, tumour necrosis factor). The gene sequence for human CRP was cloned in CRP belongs to the pentraxin protein family of oligomeric calcium-binding proteins. CRP was discovered in 193 by Tillet and Francis who observed that the sera of some acutely ill patients precipitated the capsular C polysaccharide of Streptococcus pneumoniae. The serum factor Figure 1. Structure of Human C-reactive Protein Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Reprinted from Structure 1999;7: With permission from Elsevier Science. causing precipitation was later identified as a protein and designated as C-reactive protein (CRP). CRP is part of a nonspecific immune defence mechanism which is able to bind pneumococcal capsular C polysaccharide, phosphocholine groups of membrane residues as well as chromatin in the presence of Ca++ ions. It is able to activate the classical complement pathway and function as opsonin in leukocyte phagocytosis, lymphocyte stimulation or monocyte/macrophage activation. CRP has also been detected in atherosclerotic plaques, mainly bound to partly degraded lowdensity lipoprotein. CRP may also increase the production of tissue factor by macrophages. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2;321: Du Clos TW. Function of C-reactive protein. Ann Med 2;32: Pepys MB. The renaissance of C-reactive protein. BMJ 21;322:4-5. Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive protein: Structural biology and host defence function. Clin Chem Lab Med 1999;37: Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure 1999;7: Wilkins J, Gallimore R, Moore E, et al. Rapid automated sensitivity enzyme immunoassay of C-reactive protein. Clin Chem 1998;44:

5 CRP versus Erythrocyte sedimentation rate (ESR) Increased erythrocyte sedimentation rate (ESR) is a nonspecific inflammation marker discovered much before CRP and still in frequent use as an indicator of systemic chronic infections or malignancies. ESR is primarily based on changes in the aggregation (roulette formation or piling) tendency of red blood cells. ESR depends on the concentration of positively charged serum proteins such as fibrinogen and immunoglobulins, with increased concentrations neutralising the net negative charge (zeta potential) of red blood cells. 8 CRP assay could and should replace ESR assays in many diagnostic recommendations, as CRP reflects changes in inflammatory activity faster and, being an internationally standardised immunometric assay, provides more reliable results. ESR is a complex phenomenon depending not only on the inflammatory condition but also on red cell density, plasma viscosity, red cell morphology and haemoglobin content. Reference values for ESR differ according to sex and age and are also influenced by pregnancy and obesity. The ESR assay is difficult to standardise because of its sensitivity to parameters such as assay temperature, vibration of the ESR tube, deviation of the tube from the vertical position, sample dilution and haematocrit. CRP is a better inflammation marker than ESR. mg/l mm/h iv CRP iv oral antimicrobial ESR oral antimicrobial Days Days Figure 2. Changes (mean values ± SEM) in serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) in relation to X-ray findings compatible with osteomyelitis during the first 3 days of antimicrobial therapy. Stippled areas denote the normal* ranges (<2 mg/l for CRP and <2 mm/h for ESR). The mean total duration of antimicrobial therapy was 23 days. Peltola H, et al. Simplified Treatment of Acute Staphylococcal Osteomyelitis of Childhood. Reproduced with permission from Pediatrics, Vol. 99, Page 848, Figure 1, Copyright * ) H. Peltola uses 2 mg/l as the cut-off for normal range in patients with meningitis. Publisher s comment. 9 x 1 per mm 3 % iv WBC iv oral antimicrobial X-ray changes Negative Positive Days Days Hansson L-O, Carlsson I, Hansson E, Hovelius B, Svensson P, Trydig N. Measurement of C-reactive protein and erythrocyte sedimentation rate in general practice. Scand J Prim Health Care 1995;13: Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive protein: Structural biology and host defence function. Clin Chem Lab Med 1999;37:

6 CRP versus white blood cell count (WBC) CRP in comparison with other acute-phase proteins (SAA, IL-6, procalcitonin) CRP provides more accurate information than white blood cell count (WBC) for differentiation between bacterial and viral infection. WBC values are not consistent enough to be used in monitoring the effect of antimicrobial treatment in bacterial infections (see Fig. 3). Furthermore, CRP may be used to detect acute infection and to monitor antimicrobial treatment in neutropenic or immunosuppressed patients. Gronn M et al. C-reactive protein as an indicator of infection in the immunosuppressed child. Eur J Pediatr 1986;145: Harris RI, et al. C-reactive protein rapid assay techniques for monitoring resolution of infection in immunosuppressed patients. J Clin Pathol 1984;37: Miller PR, et al. Systemic inflammatory response syndrome in the trauma intensive care unit: Who is infected? J Trauma 1999;47: Peltola H, et al. Simplified treatment of acute staphylococcal osteomyelitis of childhood. Pediatrics 1997;99: Sormunen P, et al. C-reactive protein is useful in distinguishing Gram-stain-negative bacterial meningitis from viral meningitis in children. J Pediatr 1999;134: Blood-WBC (1 9 /L) Serum-CRP (mg/l) Bacterial meningitis Patients Figure 3. Individual values of serum results of patients with Gram stain-negative bacterial and viral meningitis. Sormunen P, et al. C-reactive protein is useful in distinguishing Gram-stain-negative bacterial meningitis from viral meningitis in children. J Pediatr 1999;134: By permission of Mosby, Inc Viral meningitis Patients Acute-phase reaction is a collective designation for changes in serum protein profile and cellular immune response, encompassing symptoms like fever, tiredness and general malaise induced by infection, inflammation or trauma. Serum proteins that are upregulated or downregulated during inflammation are called positive or negative acute-phase proteins, respectively. CRP The most valuable acute-phase protein At the moment, CRP is the best known and diagnostically most valuable acute-phase protein. The group of acute-phase proteins includes besides CRP many other proteins, such as serum amyloid A (SAA), fibrinogen, procalcitonin, haptoglobin, alpha 2 - haptoglobin, alpha 1 -acid glycoprotein, caeruloplasmin, alpha 1 -antitrypsin and albumin. The disadvantage of haptoglobin (see Fig. 4), alpha 2 -haptoglobin, alpha 1 - acid glycoprotein, caeruloplasmin, alpha 1 -antitrypsin and albumin is that the differences between normal and pathological values are very small. The values measured in pathological conditions are only a few times those found in healthy individuals, and they are also determined by other (e.g. nutritional) factors in addition to infections. The concentration of CRP in serum reflects the rate of synthesis of this protein in the liver. Hepatocyte CRP synthesis is triggered by cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumour necrosis factor (TNF) secreted by monocytes/macrophages. The elevation of IL-6 concentration in serum is one of the earliest markers of inflammatory processes, detectable 1 11

7 Bacterial versus viral infections 2-3 h after onset of infection. Similarly, IL-6 concentration decreases very rapidly, almost too rapidly to be detected, to normal. Rise in CRP concentration is normally detectable 4-7 h later, depending on the sensitivity of assay. CRP both rises and decreases rapidly according to inflammation activity, which makes it a very suitable marker for detecting inflammation. Pathological values easy to detect Compared to many other acute-phase proteins, CRP has the advantage that pathological values are easy to detect since the increase in CRP concentration can be several hundredfold. The entire range for CRP (mg/l) is detectable by routine clinical chemistry analysers, whereas some other analytes, e.g. procalcitonin (ng/ml) and IL-6 (pg/ml), require different instrumentation. Serum Concentration (% change) 9 C-reactive protein Serum Amyloid A 5 ESR Haptoglobin 1 C3 Albumin Days post stimulation Figure 4. Major components of the acute-phase response. Serum concentrations of CRP and SAA rise rapidly several hundred percent above baseline values after an inflammatory stimulus. Haptoglobin and complement (C3) rise more slowly and to a lesser extent. Albumin levels drop. ESR shows a slower rise and return to normal compared with CRP. ESR units are millimeters/h. Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997;16: By permission of Lippincott, Williams & Wilkins ESR units Determination of SAA is today cumbersome because of lack of methods for routine measurements.the routine methods for CRP are today mostly immunoturbidimetric or nephelometric. The introduction of the international standard IFCC CRM 47 has made the available CRP assays very reliable. Hansson L-O, Carlsson I, Hansson E, Hovelius B, Svensson P, Trydig N. Measurement of C-reactive protein and erythrocyte sedimentation rate in general practice. Scand J Prim Health Care 1995;13: Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive protein: Structural biology and host defence function. Clin Chem Lab Med 1999;37: Yamada T. Serum amyloid A (SAA): a concise review of biology, assay methods and clinical usefulness. Clin Chem Lab Med 1999;37: CRP has proved useful in differentiating bacterial infections from viral infections. Bacterial infection increases serum CRP concentration, whereas viral infection does not. The rise in CRP usually corresponds to the extent of bacterial infection. Bacterial infections limited in scope may in some cases be accompanied by normal or low CRP values. However, it may be that adeno-virus, as some herpes viruses, are able to cause such massive tissue injury that CRP production is triggered. Among the most important qualities of CRP are its high sensitivity and high negative predictive value. Measurement of CRP greatly facilitates the management of infectious diseases, and it can help to avoid 12 13

8 CRP in monitoring antibiotic therapy CRP (mg/l) bacterial N 23 viral N 19 = pretreatment ab mean 147 Figure 5. First serum CRP determinations of 42 children with proven infection of the CNS. Unpublished data by Dr H Peltola. unnecessary use of antimicrobial agents in many patients with viral infections. Determination of serum CRP is one of the few diagnostic tests that can be used at the early phase of infection to reliably ascertain whether virus or bacteria is the causative agent and to decide whether or not to start antibiotic therapy. Prescription of antibiotics in cases of viral infection is pointless and carries the potential risk of generating antibiotic resistance in pathogenic bacteria. Sormunen P, et al. C-reactive protein is useful in distinguishing Gram-stain-negative bacterial meningitis from viral meningitis in children. J Pediatr 1999;134: If severe bacterial infection is suspected, antibiotic therapy is normally started immediately even if CRP or other inflammation markers are not elevated. As the induction of CRP synthesis in the liver has a lag period of 6-12 h, it is not possible to detect infection during the first hours after its onset. CRP values within the reference range in serial assays at 24 h and 48 h have been shown to be reliable evidence allowing discontinuation of antibiotic therapy in neonates with suspected septicaemia. With blood culture, septicaemia can not be excluded until after h of incubation. Monitor the CRP concentration daily Serial CRP determination is the most useful means of monitoring patients for complications during antimicrobial treatment of bacterial infections. The amount of CRP in the bloodstream follows the circulating levels of inflammatory lymphokines with a lag of a few hours. Lymphokine secretion by activated leukocytes decreases soon after pathogens have been eliminated and the situation has normalised. If, however, treatment is not successful, the CRP level remains high for several days and may even increase if the infection takes a turn for the worse. Monitoring serial CRP values can alert the physician to complications and predict the outcome earlier than clinical signs, for instance. CRP measurements have even proved to be useful in clinically challenging conditions complicated by neutropenia and immunosuppression

9 CRP (mg/l) AM * * * * * * * : p<.1 Complicated BM Uneventful BM Days post stimulation Figure 6. Mean daily CRP concentrations in bacterial meningitis (BM) with an uneventful (N=38) or complicated (N=22) course of illness, as compared with aseptic meningitis (AM) (N=16). Roine I, et al. Pediatr Infect Dis J 1991;1: By permission of the author and the publishers, Williams & Wilkins. Requirements for monitoring the course of an illness by CRP assay: 1. Quantitative measurement of CRP concentration in serum 2. Taking whole blood samples by finger pricks or from the heel makes serial sampling less unpleasant for infants. 3. The test results should be available rapidly, preferably within one hour. If the clinician receives the result the next day, most of the informative value of the CRP test is available too late. Bomela HN, Ballot DE, Cory BJ, Cooper PA. Use of C-reactive protein to guide duration of empiric antibiotic therapy in suspected early neonatal sepsis. Pediatr Infect Dis J 2;19: Gronn M et al. C-reactive protein as an indicator of infection in the immunosuppressed child. Eur J Pediatr 1986;145: Harris RI, et al. C-reactive protein rapid assay techniques for monitoring resolution of infection in immunosuppressed patients. J Clin Pathol 1984;37: Philip AGS, et al. Use of C-reactive protein in minimizing antibiotic exposure: Experience with infants initially admitted to a well-baby nursery. Pediatrics 2;16:1-5. Roine I, et al. Serial serum C-reactive protein to monitor recovery from acute hematogenous osteomyelitis in children. Pediatr Infect Dis J 1995;14:4-4. Singh UK, Sinha RK, Suman S, Singh VK. C-reactive protein as an indicator of complications in bacterial meningitis. Indian Pediatr 1996;33:

10 CRP in various clinical settings Severe infections such as septicaemia, endocarditis and osteomyelitis Many systemic diseases involve a bacteraemic phase, for instance some cases of pneumonia, bacterial meningitis, enteric fever and septic arthritis. The symptoms may be almost identical to those of viral infection. Markedly elevated CRP concentrations (>1 mg/l) usually suggest bacterial or fungal infections in the absence of other overt inflammatory conditions. Nevertheless, some patients with serious bacterial infections may have only moderately elevated or even normal CRP concentration. This is particularly true during the first 6-12 h after the onset of infection. Compared with ESR, CRP is a more sensitive marker for diagnosis of infective endocarditis especially at an early phase (>12 h) of the disease. CRP is normalised sooner than ESR after the pathogens have been eliminated. Serial CRP determinations are the most effective way of follow up the patient's condition if complications occur during treatment, also accounting for the interindividual differences in normal levels of CRP. This should be kept in mind especially in doubtful cases and with premature infants in whom the rise in CRP concentration during septicaemia may not be as great as in adults. The measured CRP value should always be evaluated against group-specific reference values. Bone infection is characterised by a progressive infectious process resulting in inflammatory destruction of bone, bone necrosis and new bone formation. CRP may rise to 1 times normal levels in cases of osteomyelitis. Markedly elevated CRP concentrations (>1mg/l) suggest severe bacterial infection. Hogevik H, Olaison L, Andersson R, Alestig K. C-reactive protein is more sensitive than erythrocyte sedimentation rate for diagnosis of infective endocarditis. Infection 1997;25:14/82-17/85. Posen R, delemos RA. C-reactive protein levels in the extremely premature infant: Case studies and literature review. J Perinatol 1998;18: Peltola H, Unkila-Kallio L, Kallio MJ. Simplified treatment of acute staphylococcal osteomyelitis of childhood. Pediatrics 1997;99: Perry M. Erythrocyte sedimentation rate and C-reactive protein in the assessment of suspected bone infection are they reliable indices? J R Coll Surg Edinb 1996;41: Meningitis CRP measurements have proved useful in meningitis because CRP is capable of distinguishing Gram stain-negative bacterial meningitis from viral meningitis with high sensitivity (96%), high specificity (93%) and high negative predictive value (99%) in children over 3 months of age. No other laboratory tests reached these performance levels. Serial measurements showing CRP concentrations <2 mg/l suggests viral meningitis. Peltola H. C-reactive protein for rapid monitoring of infections of the central nervous system. Lancet 1982;1: Sormunen P, et al. C-reactive protein is useful in distinguishing Gram-stain-negative bacterial meningitis from viral meningitis in children. J Pediatr 1999;134:

11 Pneumonia and bronchitis Pneumonia Respiratory infections pose a problem because many acute lower respiratory infections are mixed infections. CRP data can contribute significantly to diagnosis, along with history and physical examination. CRP measurement is recommended as the first-line method of screening in cases of suspected pneumonia. CRP concentrations of approx. >6 mg/l suggest pneumonia of bacterial origin. Korppi M, et al. White blood cells, C-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children. Eur Respir J 1997;1: Bronchitis Acute bronchitis is rarely caused by bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae, and it is seldom due to bacterial infections severe enough to significantly increase the level of CRP in serum. A negative CRP test is therefore useful in distinguishing between pneumonia and bronchitis. Measurement of CRP is recommended to reduce the prescribing of antibiotics in acute bronchitis and unspecific upper respiratory tract infections. It is recommended that CRP be used as a diagnostic tool in primary care in cases of lower respiratory tract infections when differentiating between pneumonia and bronchitis. Jonsson JS, et al. Acute bronchitis in adults. How close do we come to its aetiology in general practice? Scand J Prim Health Care 1997;15: Melander E, et al. Medical audit changes physicians prescribing of antibiotics for respiratory tract infections. Scand J Prim Health Care 1999;17: Sinusitis and bacterial pharyngitis (sore throat) Sinusitis Haemophilus influenzae is one of the most common causes of acute maxillary sinusitis. Serum CRP can in these cases rise to approx. 2 mg/l. Higher CRP values (>4 mg/l) associated with acute maxillary sinusitis should alert the physician to the possibility of causation by Streptococcus pyogenes or Streptococcus pneumoniae, since if left untreated, such cases may progress to sinus empyema. Elevated CRP values seem to be a better criterion for antibiotic treatment than is solely clinical examination. Hansen JG, et al. Predicting acute maxillary sinusitis in a general practice population. BMJ 1995;311: Savolainen S, et al. Do simple laboratory tests help in etiologic diagnosis in acute maxillary sinusitis? Acta Otolaryngol 1997;suppl 529:

12 Bacterial pharyngitis (sore throat) The measurement of CRP in a primary care setting can improve diagnostic accuracy in infections of the throat. It can increase the proportion of patients diagnosed correctly and treated adequately as compared with purely clinical diagnoses. Unnecessary and expensive use of antibiotics, which also supports the development of resistant bacterial strains, can thus be reduced. A CRP level of approx. 35 mg/l could be a useful cut-off point for differentiating between bacterial and nonbacterial pharyngitis. Gulich MS, et al. Improving diagnostic accuracy of bacterial pharyngitis by near patient measurement of C-reactive protein (CRP). Br J Gen Pract 1999;February: Urinary tract infections Measurement of serum CRP is a reliable laboratory test for differentiating lower general urinary tract infection (cystitis) from more serious upper urinary tract infection (pyelonephritis). CRP values higher than approx mg/l suggest pyelonephritis. Chih-Wei Y, et al. Urinary tract infection in children. J Microbiol Immunol Infect 1999;32: Jodal U, et al. Level diagnosis of symptomatic urinary tract infections in childhood. Acta Paediatr Scand 1975;64: Pelvic inflammatory disease (PID) In assessing the treatment of pelvic inflammatory disease (PID), determination of CRP has precedence over WBC, ESR and body temperature. CRP increases in PID, and the changes in CRP value reliably reflect changes in the patient's clinical condition. Reljic M, et al. C-reactive protein and the treatment of pelvic inflammatory disease. Int J Gynecology & Obstetrics 1998; 6: Rheumatoid arthritis and systemic lupus erythaematosus (SLE) Rheumatoid arthritis CRP and ESR are both widely used in the management of rheumatoid arthritis. ESR is strongly correlated with certain laboratory values that do not reflect the degree of inflammation but are known to influence ESR directly, including immunoglobulins, rheumatoid factor (RF) and haemoglobin. CRP, on the other hand, is more strongly correlated with composite disease activity, grip strength and joint count. This suggests that the acute-phase is better measured with CRP. Immunoglobulins do not generally reflect the acute phase to any significant degree, and RF is, similarly, not an acute-phase 22 23

13 marker. These latter factors and ESR can be considered as markers of disease severity and chronicity. CRP appears to be the test of choice where measurement of the acute phase is concerned. van Leeuwen MA, et al. Acute phase proteins in the monitoring of inflammatory disorders. Baillière s Clin Rheumatol 1994;8: Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. J of Rheumatol 1997;24; Systemic lupus erythaematosus (SLE) Systemic lupus erythaematosus (SLE) is a disorder in which often only a modest or even no elevation of CRP is found despite active disease, whereas ESR is elevated in most cases. Patients with SLE are, however, capable of significant CRP responses during bacterial infections or other inflammatory processes not related to SLE activity. Some studies have found that CRP concentrations are often higher in disease exacerbations accompanied by serositis than in exacerbations without serositis, with concentrations exceeding 6 mg/l during active serositis. Bravo MG and Alarcon-Segovia D. C-reactive protein in the differential diagnosis between infection and reactivation of SLE. J Rheumatol 1981;8: van Leeuwen MA, et al. Acute phase proteins in the monitoring of inflammatory disorders. Baillière s Clin Rheumatol 1994;8: CRP in myocardial infarction CRP rises in acute myocardial infarction, correlating positively with infarct size in the absence of thrombolytic treatment. The CRP response is lower in patients with an open infarct-related coronary artery than in patients with a fully occluded infarctrelated coronary artery. Serum CRP concentration averages 16 mg/l in extensive infarction and 4 mg/l in limited infarction. CRP is also an independent predictor of survival after ischaemic stroke. Survival has been found to be significantly worse in patients with CRP exceeding approx. 1 mg/l than in those with CRP less than 1 mg/l. Mild elevation in serum CRP has recently been shown to predict atherosclerotic diseases. See section on ultrasensitive CRP below. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2;321: Haverkate F. Low-grade acute-phase reactions in arteriosclerosis and the consequences for haemostatic risk factors. Fibrinolysis 1992;6(Suppl 3): Muir KW, et al. C-reactive protein and outcome after ischemic stroke. Stroke 1999;3: Pepys MB. The renaissance of C reactive protein. BMJ 21;322:4-5. Pietilä K, et al. Intravenous streptokinase treatment and serum C-reactive protein in patients with acute myocardial infarction. Br Heart J 1987;58: Ridker PM, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;312: Rifai N, Ridker PM. Proposed cardiovascular risk assessment algorithm using highsensitivity C-reactive protein and lipid screening. Clin Chem 21;47:28-3. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 21;47:

14 Surgery and postoperative infections, trauma Tissue injury Serum CRP concentration is significantly elevated in extensive burns. CRP decreases by the third day in burn patients who do not develop infection and tends to fall progressively with healing over one month. A second peak will develop if infection occurs as a later complication of the burn, suggesting a role for CRP determinations in monitoring the course of healing. An increase in CRP levels can predict septicaemia in patients with burns, allowing the treatment of septicaemia to be started sooner. CRP (mg/dl) Figure 7. Time course of CRP serum levels in representative patient No. 1. Neely AN, et al. Efficacy of a rise in C-reactive protein serum levels as an early indicator of sepsis in burned children. J Burn Care Rehabil 1998;19:12-1. By permission of Lippincott, Williams & Wilkins. Please note that in this figure the unit of CRP concentration is mg/dl. Publisher s comment Days Postburn Burn Surgery Surgery Neely AN, et al. Efficacy of a rise in C-reactive protein serum levels as an early indicator of sepsis in burned children. J Burn Care Rehabil 1998;19: Preoperative and postoperative infections CRP usually rises within 6 h after surgery. In the absence of complications, CRP values then decline and normalise within a couple of days. On the other hand, CRP remains elevated much longer if the postoperative course is complicated by infection. The incidence of postoperative infections has been found to be significantly higher in patients with increased preoperative CRP levels than in those with normal preoperative levels. Patients with higher preoperative CRP levels also remain in hospital significantly longer than those with normal preoperative levels. CRP (mg/l) Figure 8. Mean preoperative levels of CRP in plasma in cardiac surgical patients with elevated preoperative CRP levels (>8 mg/l, red bars) and in patients with normal preoperative CRP levels ( 8 mg/l, blue bars). The data are presented as means ± standard error. *p<.5, between groups. (PRE = the day before the operation.) Fransen EJ, et al. Enhanced preoperative C-reactive plasma levels as a risk factor for postoperative infections after cardiac surgery. Ann Thorac Surg 1999;67: Reprinted by permission from the Society of Thoracic Surgeons. * Pre * * Postoperative days Fransen EJ, et al. Enhanced preoperative C-reactive protein plasma levels as a risk factor for postoperative infections after cardiac surgery. Ann Thorac Surg 1999;67, * * * 26 27

15 Appendicitis Transplantation CRP is a useful marker in monitoring the posttransplant period. After an increase during the first three days after transplantation, CRP concentration starts to decrease. If CRP concentration does not decrease, early rejection can be suspected. Pretransplant measurement of CRP baseline concentration is recommended as a reference for posttransplant values. CRP concentrations should be evaluated on a withinpatient basis rather than by application of a fixed range window. CRP assay is rapid, simple and economical, and the samples are stable. Mean Creatinine um/l Figure 9. Median scrp and mean creatinine levels for patients with excellent primary function and no complications. Harris KR, et al. Serum C-reactive protein. A useful and economical marker of immune activation in renal transplantation. Transplantation 1996;61: By permission of Lippincott, Williams & Wilkins. CRP (median) Creatinine (mean +/- SEM) Days post transplant Harris KR, et al. Serum C-Reactive protein. A useful and economical marker of immune activation in renal transplantation. Transplantation 1996;6: Median CRP ug/ml Acute appendicitis is usually diagnosed on the basis of a surgeon s clinical impression. Today, the negative laparotomy rate because of clinical diagnosis is still 15% to 25%. Patients with perforated appendixes have high CRP values exceeding approx. 1 mg/l. In nonperforated appendicitis, CRP is slightly elevated (>2 mg/l). The presence of acute appendicitis is unlikely in a patient with normal WBC and CRP value, even if clinical symptoms and signs suggest acute appendicitis. Serum CRP levels can be used to support a clinical diagnosis regarding acute appendicitis, thereby reducing the number of unnecessary laparotomies. It is advisable to observe atypical patients with serial clinical examinations and CRP tests when in doubt about the diagnosis. CRP measurements as a routine laboratory test are recommended in patients with a suspected diagnosis of acute appendicitis. CRP values exceeding approx. 1 mg/l suggest a perforated appendix. Gurleyik E, et al. Accuracy of serum c-reactive protein measurements in diagnosis of acute appendicitis compared with surgeon s clinical impression. Dis Colon Rectum 1995;38:

16 CRP in point-of-care testing Rapid diagnosis When a patient is seriously ill, it is of utmost importance that treatment can be started as soon as possible. CRP is a valuable tool in ensuring a correct diagnosis and determining the need for further treatment. It is therefore crucial that the result of the CRP test is available to the physician as quickly as possible. The increased pressure for rapid diagnosis and treatment has in many cases removed the CRP test from the clinical laboratory to the point-of-care setting. In children In paediatrics, CRP is a convenient diagnostic tool because of the small volume of sample required and the suitability of whole blood samples for the test. A short therapeutic turn-around time for the CRP result is often necessary for an early and rapid intervention to inhibit the progression of severe bacterial infections in children. Furthermore, as children are susceptible to frequent respiratory tract infections, and primary care clinics are often contacted because of these, rapid CRP tests may be used to differentiate between viral and bacterial infections and, consequently, to reduce unnecessary antimicrobial treatments. In geriatry Elderly patients sometimes have massive infections with no fever, no abnormal cell counts etc. A CRP test can help the physician to detect bacterial infections, which, if left untreated, contribute to excessive morbidity in the elderly. Economic savings From the point of view of physicians and healthcare planners, an increased use of point-of-care testing in general practice is desirable for monitoring patients who are today often discharged sooner than previously from hospitals and those who are moved from hospital outpatient clinics to general practice. Reduced use of antibiotics With the increasing occurrence of bacteria resistant to antimicrobial treatment, it has become even more important to measure CRP in all cases of suspected bacterial infection. Overuse of antibiotics can be reduced by using CRP tests to rule out viral infections where antibiotics are of no benefit. Therapeutic turn-around time (TAT) The therapeutic turn-around time (TAT) should be very short, with the CRP assay being quick to perform, the test results being obtained quickly and the therapeutic decision being made during the patient s first visit. Definition of point-of-care testing Point-of-care testing denotes any analytical procedure performed for, or by, a patient outside the traditional clinical laboratory near the patient. 3 31

17 Ultrasensitive CRP Various acronyms and terms are used when referring to point-of-care testing: 1) point-of-care (POC) or point-of-care testing (POCT) 2) near-patient testing (NPT) 3) decentralised testing Requirements for CRP assays in point-of-care testing: easy and reliable performance of the test quantitative results use of whole blood test result available in minutes minimal maintenance of the instrument Ballou SP, Kushner I. Chronic inflammation in older people: recognition, consequences, and potential intervention. Clin Geriatr Med 1997; 13(4): Gulich MS, et al. Improving diagnostic accuracy of bacterial pharyngitis by near patient measurement of C-reactive protein (CRP). Br J Gen Pract 1999; February: Hobbs FD, et al: Reliability and feasibility of a near patient test for C-reactive protein in primary care. Br J Gen Pract 1996;46: Price CP, Hicks JM. Point-of-Care Testing. AACC Press, CRP values up to 5-1 mg/l are considered to be within the reference interval when healthy persons without acute infections are concerned. It has been found that lower values are associated with an increased risk of atherothrombotic events and they are also clinically significant in osteoarthritis. The current reference range for healthy people is 1 mg/l. A repeatedly measured CRP value of 2 3 mg/l may be a sign of an ongoing inflammation indicating a possible risk of atherosclerosis. With neonates, birth is considered to be the first acute-phase reactant in the newborn s life. The CRP reference range is considered to be lower in healthy neonates than in adults. An increase to 2 3 mg/l during the first days of life may indicate septicaemia. Benitz WE, et al. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998;12:1-1. Chenillot O et al. High sensitivity C-reactive protein: biological variations and reference limits. Clin Chem Lab Med 2;38: Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2;321: Fichtlscherer S, Zeiher AM. Endothelial dysfunction in acute coronary syndromes: association with elevated C-reactive protein levels. Ann Med 2;32: Haverkate F. Low-grade acute-phase reactions in arteriosclerosis and the consequences for haemostatic risk factors. Fibrinolysis 1992;6(Suppl. 3): Mendall MA, et al. C Reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. N Engl J Med 1996;312: Pepys MB. The renaissance of C-reactive protein. BMJ 21;322:4-5. Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;312: Rifai N, Ridker PM. Proposed cardiovascular risk assessment algorithm using highsensitivity C-reactive protein and lipid screening. Clin Chem 21;47:28-3. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 21;47:

18 Orion Diagnostica s CRP assays Immunoturbidimetric assays For clinical chemistry analysers Separate reagents For clinical chemistry analysers QuikRead CRP For point-of-care testing Turbox CRP For small to medium sized laboratories Immunoturbidimetric CRP Kit... Cat. No Measuring range 8-16 mg/l Applications available for different analysers Immunoturbidimetric Ultrasensitive CRP Kit... Cat. No Measuring range -1 mg/l Limit of quantification.1 mg/l Applications available for different analysers CRP Antiserum...Cat. No ml CRP Calibrator Set...Cat. No different CRP concentrations (5-2 mg/l) CRP Control...Cat. No Low level, 1 ml CRP Control...Cat. No High level, 1 ml CRP Buffer...Cat. No ml Ultrasensitive CRP Control...Cat. No ml QuikRead 11 Instrument...Cat. No. 64 QuikRead CRP Kit...Cat. No tests QuikRead CRP Kit...Cat. No tests, including capillaries & plungers QuikRead CRP Control...Cat. No Approx. 49 mg/l For USA only: QuikRead 11 Instrument...Cat. No. 688 Quikread CRP Kit...Cat. No tests, including capillaries & plungers QuikRead CRP Control Set...Cat. No Turbox Plus Analyser...Cat. No Turbox CRP Kit...Cat. No QuikRead CRP Verification Set...Cat. No