Journal of Clinical Laboratory Analysis 4:231-235 (1990)
Potential Clinical Applications of C-Reactive Protein J.M. Okamura, J.M. Miyagi, K. Terada, and Y. Hokama John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu, Hawaii This article reviews the clinical applications of C-reactiveprotein (CRP).This acute-phase protein is a distinct and sensitive marker for inflammation and tissue injury. It is a simple, fast, and relatively inexpensive latex aggluti-
Key words:
Acute-phaseprotein, CRP, inflammation,injury, diagnostic screening, serial testing
INTRODUCTION C-reactive protein (CRP) was first detected in 1930 as a marker for pneumococcal pneumonia (1). It was later shown that, in the presence of calcium ions, this protein would complex with pneumoccal C-polysacchride, and thus the term C-reactive protein was derived (2). CRP has since been demonstrated in a multitude of disease states, the nonspecific hallmarks of which are inflammation and tissue injury. Thus, CRP is considered one of the acute-phase proteins, which includes other serum proteins and glycoproteins that increase during an acute inflammatory episode (3,4). CRP is synthesized by hepatocytes. It has been detected in serum, CSF, and synovial, amniotic, pleural, ascitic, and blister fluids (5). It does not, however, cross the placental membrane (6,7). It is present in healthy individuals, with normal values progressively increasing with age (8,9). CRP has been shown to be elevated within hours of disease onset (10). It increases exponentially with a doubling time of 8.2 hours ( 1 1). It is also rapidly cleared, with a half-life of approximately 6 hr (1 2,13). Although CRP has been evaluated by a number of techniques, most clinical laboratories utilize the latex agglutination test. While this test may lack sensitivity, it is relatively inexpensive and can provide rapid results (14,15). Another commonly used test for CRP determination is the automated laser nephelometer. Once the patient’s serum is obtained, no further steps are required prior to running the test on the nephelometer. The turnaround time in a routine laboratory is about 4 hr, and the test costs approximately $31 sample. Although not commonly found in clinical laboratories, this test is both inexpensive and clinically feasible (16). CRP may increase as much as 2,000-fold in certain diseases, which suggests a significant function; however, CRP’s definitive effects have been elusive. It has been suggested that CRP may function as an opsonin (5,17), CRP has been shown to bind to various bacteria and tissue membranes and to enhance phagocytosis. It also has the ability to activate the classical complement pathway, with subsequent binding and solubili0 1990 Wiley-Liss, Inc.
nation test. The aspects of CRP reviewed include diagnostic support, serial measurements to evaluate disease course and therapeutic response, and screening studies.
zation of DNA (5,18). In addition, various other immune system functions have been also associated with CRP during acute inflammation (5).
CRP VERSUS OTHER INFLAMMATORY FACTORS CRP levels in relation to other inflammatory factors have been extensively examined. The best correlation appears to be between CRP, polymorphonuclear cells, alpha-glycoprotein, and the erythrocyte sedimentation rate (ESR). In comparison with the ESR, CRP appears earlier following onset of disease; returns to normal values earlier; has greater sensitivity; has an extended time limit for the sample to be tested (the blood sample for ESR must be tested within 2 hr after blood is drawn); and is not affected by lowered red blood cell counts, changes in serum protein concentrations, or immunologic status (5,19,20). Thus, although infrequently utilized, CRP should be seriously considered as an alternative or complement to the various other more traditional tests.
CLINICAL ASPECTS OF CRP The clinical usefulness of CRP lies in its ability to reveal early inflammation and tissue injury when other clinical parameters are equivocal. There are three general applications of CRP analysis. First, it can be used as a diagnostic support tool. Second, serial measurements make it possible to follow exacerbations, complications, and/or efficacy of treatment. Third, the CRP test can be used as a screening tool.
Diagnostic Support Diagnostically, CRP is useful in differentiating between bacterial and viral infections, as the former tend toward invasive
Received December 26, 1989; accepted January 2, 1990. Addreas reprint requests to Y. Hokama, Ph.D., Department of Pathology, JABSM, University of Hawaii, Manoa, Honolulu, HI 96822.
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properties that result in inflammation and injury with a subsequent CRP elevation not seen in the latter. For example, when a child presents with a fever requiring a sepsis evaluation, the diagnostic blood culture requires 48 hr and may prove falsely negative. In such cases, studies have shown that CRP is a sensitive and rapidly reacting index in bacteremic infections. The sensitivity approaches 99%- 100%.False-negative results may be due to skin contamination, or may possibly represent a small fraction of cases of real septicemia in which CRP has not had time to increase. However, CRP is not specific. The reason CRP may increase in some viral infections is not fully understood, but such increases may partially be explained by a secondary bacterial infection. Nevertheless, the increased CRP levels with some viral infections emphasize the need to pay more attention to a single unincreased value than an increased CRP value. It has been concluded that, if the history of illness is at least 12 hr and two or more CRP values (taken a few hours apart) are negative, invasive bacterial disease is very unlikely (20). The only exception is in neonates. During the first month of life, CRP is not totally reliable, although it is still useful because CRP is better than other nonspecific laboratory tests (20,21). In adults, CRP appears to be the most sensitive of plasma proteins as an indicator of systemic bacterial infection (22). Studies have shown that CRP sensitivity can be increased by the use of a four-part sepsis screen (white blood cell count, immatureltotal neutrophil ratio [I/T ratio], CRP level, and ESR), which has produced a negative predictive value of loo%, compared with CRP alone at 99%; this small improvement may be significant to clinicians who do not want to miss even a single case (23). As CRP is not transferred across the placenta, a positive CRP value detected within the first few hours of life in an infant whose mother has presented with prolonged rupture of amniotic membranes (PROM) and/or amnionitis can be regarded as a marker for neonatal bacterial infection (6,24,25). After the first day of life, however, a positive CRP may also be caused by various other conditions. In contrast, elevated maternal CRP values before delivery predict infectious morbidity in only 8%-29% of patients, and up to 18% of patients with serious infections may be misdiagnosed as having normal CRP values before delivery (15,26). CRP is beneficial in differentiating bacterial from viral meningitis (27-30). CRP is highly sensitive. False-positive results, however, are not of overwhelming concern, since other bacterial infections may be equally life-threatening and also require prompt antibiotic therapy. The difficulty comes with the occasional false-negative result, which could lead to withholding of antibiotics from a patient with bacterial meningitis. Therefore, the clinician must evaluate the patient as a whole and recognize the inherent limitations of a test related to the inflammatory reaction of the host (27,31). Both serum and CSF CRP values are of diagnostic significance. However, some studies suggest that the assay of CSF is less discriminatory due to local consumption of CRP, resulting in levels that may
be misleadingly low (28,32). Regardless, the CRP test is more rapid than any other laboratory test available for detecting bacterial meningitis, except for the Gram stain; however, CRP is much more sensitive (97%) than the Gram stain (80%). When computerized tomography (CT) scans are equivocal, CRP may be useful in differentiating between a tumor and an abcess. A significant rise in CRP levels has been observed in most cases of bacterial brain abcesses; the most pronounced rise was recorded early in the course of the disease (cerebritis) before a well-defined abcess membrane was formed (33). Nonmetastatic tumors, on the other hand, will show little if any elevation of CRP (34). The relationship between the rise in creatinine kinase-MB fraction (CK-MB) and CRP in patients experiencing myocardial infarction (MI) has been studied (35,36). The results show that a rise in CRP in cases of chest pain without a rise in CK-MB is strongly suggestive of a noninfarctive or noncardiac lesion. In addition, DeBeer et al. (35) reported that, because CRP levels peaked at a mean time of 50 hr after the onset of chest pain following an MI, in comparison with 15 hr to peak CK-MB, CRP may be useful in cases where infarction is only suspected when CK-MB values may have returned to normal. With respect to the above findings, deliberate care must be taken to rule out other possible sources of inflammation or injury such as urinary tract infection, respiratory tract infection, otitis media (37,38), and other diseases that may also produce a elevated CRP level.
Serial Measurements Serial measurements of CRP may provide valuable information regarding the course of a disease with respect to exacerbations, complications, and the efficacy of treatment. The typical CRP elevation pattern is a rapid rise within hours of disease onset. CRP then remains elevated as long as the disease state remains. An uneventful recovery is heralded by levels that fall rapidly. A persistent elevation or a re-elevation is a warning sign indicating that further investigation may be necessary. The value of serial CRP determinations in postoperative patients who have undergone cardiac surgery is well-established (39-41). Studies have demonstrated the usefulness of CRP in predicting postoperative infectious complications before the onset of clinical symptoms. CRP has also been shown to be of greater diagnostic value for infection than a rise in white blood cells or temperature in open-heart surgery patients during their post operative course (42). In patients undergoing total hip arthroplasty procedures, CRP was found to be useful post-operatively in differentiating between septic loosening of the hip, which significantly elevated CRP levels, and mechanical loosening, in which CRP remained normal (43). The value of CRP determinations in transplant recipients has also been investigated (44-48). In bone marrow transplant recipients, low CRP coupled with high IgE levels can
C-Reactive Protein Applications
differentiate graft-versus-host disease from sepsis, which presents with high CRP and low IgE levels (47). Quantitative CRP measurements are also useful. Renal allograft recipients with CRP values exceeding 60 ng/ml are much more likely to have a serious complication other than acute rejection alone (48). In the field of rheumatology, studies have been done comparing serum and synovial fluid CRP concentrations. These have shown the possibility that, as in meningitic CSF, CRP is either selectively bound in synovium or specifically consumed in a synovial fluid, which may play a role in rheumatoid inflammation (49,50). Serum CRP has been shown to correlate significantly with radiographic changes in rheumatoid arthritis (51); it also has a significant positive correlation with rheumatoid arthritic disease as a whole (49-52). CRP determinations also may play a valuable role in the field of oncology (34,53-55). The combination of serum alphafetoprotein and CRP levels was shown to be effective in differentiating patients with hepatocellular carcinoma from those with benign liver diseases. CRP levels were also found to decrease after successful tumor resection (53). Quantitative CRP levels have been found to increase with tumor extent in patients with pancreatic cancer and thus may help in estimating progression of a tumor (54). Serial measurements may be used to monitor the course of practically any disease that possesses an inflammatory component. Examples include endocarditis, where studues have shown that serial CRP measurements are of more value than estimations of serum bacterial titer both in prognosis and in predicting continuing infection in infective endocarditis (56,57). In cystic fibrosis, the CRP concentration was highly correlated with the Shwachman clinical evaluation score, forced vital capacity as a percentage of the predicted value, and the Chrispin-Norman x-ray score. A rising CRP appears to be a simple objective index of worsening clinical condition, whereas white cell count and ESR were not found to be useful. Serum concentrations may be used as early markers of deterioration in patients with cystic fibrosis who are not yet severely affected; in the absence of pulmonary excerbation, CF is not associated with raised CRP values (58,59). CRP has been shown to be a useful aid in assessing the severity of acute pancreatitis (60-62). An increase in CRP has been shown to discriminate between mild pancreatitis and hemorrhagic pancreatritis, with an increase to greater than 250 mg/L being highly suggestive of extensive pancreatic necrosis. In inflammatory bowel diseases, CRP has been shown to be valuable in determining the extent of disease in monitoring the response to treatment, in predicting outcome, and in defining prognostic subgroups of patients (63,641.
CRP Screening The use of CRP as a screening test has been investigated, but studies to assess the value of such tests have met with
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limited success (5,39). One study has shown preoperative screening CRP measurements in cardiac surgery patients to be predictive of postoperative infectious complications (39). However, these observations have been challenged (65). The CRP test has been proposed as a screen for blood donors (5), but further investigation is necessary. CRP screening has not been shown to adequately assess ongoing active or chronic disease in the elderly (65). This is possibly due to both the unpredictability of CRP with advancing age and the greater prevalence of inflammatory states in the elderly population. Thus, the role of CRP in screening for occult inflammation, general health status, and blood donors has so far proven minimal and requiring further study.
CONCLUSIONS In summary, while CRP is a frequently overlooked test, it has been shown to be an invaluable tool in diagnostic support and in aiding the evaluation of disease course and therapeutic response. In addition, the simplicity, speed, and relative inexpensiveness of the test make it clinically feasible and practical. CRP’s properties as a distinct and sensitive marker for inflammation and tissue injury make its use in diagnosis, prognosis, course, treatment efficacy, and screening virtually limitless. The future use of CRP as a routine laboratory test in patient evaluation appears imminent, and knowledge of its applications will likely become a necessity for modem-day practitioners in all fields of medicine (67,68).
ACKNOWLEDGMENTS Supported in part by the Hokama-Yagawa Memorial Fund, UHF.
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9. Unten S, Hokama Y: An enzyme immunoassay for C-reactive protein analysis. J Clin Lab Anal 1:136-139, 1987. 10. Peltola H, Jaakkola M: Serious bacterial infections: C-reactive protein as a serial index of severity. Clin Pediatr 27:532-537, 1988. 11. Kuschner I. Broder ML, Karp D: Control of the acute-phase response: Serum C-reactive protein kinetics after acute myocardia infarction. J Clinlnvest73:191, 1978. 12. Hokama Y: Methods of assay and role of acute-phase C-reactive protein in human disease. In Immunologic Analysis: Recent Progress in Diagnostic Laborafory Immunology, RM Nakamura, WR Ditto. ES Tucker, eds. Masson, New York, 1982, pp 239-257. 13. Chelladurai M, MacIntyre SS, Kushner I: In vivo studies of serum C-reactive protein turnover in rabbits. J Clin Invest 71:604, 1983. 14. Diaz V, Alvarez C. Sanz R, Alonso T: Use of cerbrospinal fluid Creactive protein in laboratory diagnosis of bacterial meningitis. Clin Chem 34:1357, 1988. 15. Kornman L, Jacobs V, Hodgson P, et al: Chorioamnionitis: How useful is the determination of C-reactive protein: Aust N Z J Obsret Gynaecol 2n:4s-48, 1988. 16. Mustard RA, Bohnen JMA, Haseeb S, Kasina R: C-reactive protein levels predict postoperative septic complications. Arch Surg 122:69-73, 1987. 17. Hokama Y, Honda SAA, Hanakahi LA, Terada K: C-reactive protein and platelet activating factor complexes induced production and release ofinterleukin-I by humanmonocytes.JC/in LabAnal2:155-160, 1988. 18. Robey FA, Jones KD, Steinberg AD: C-reactive protein mediates the solubilization of nuclear DNA by complement in vitro. J Exp Med 161:1344, 1985. 19. Struelens M, Delville J, Laypaert P, Wybran J: Granulocyte elastase compared to C-reactive protein for early diagnosis of septicemia in critically ill patients. Eur J Clin Microbiollnfect Dis 7:193-195, 1988. 20. Peltola H, Jaakkola M: C-reactive protein in early detection of bacteremic versus viral infections in immunocompetent and compromised children. Jfediarr 113:641-646, 1988.. 21. Mathers NJ, Pohlandt F Diagnostic audit of C-reactive protein in neonatal infection. E u r J Pediatr 146:147-151, 1987. 22. Gozzard DI, Liu Yin JA, Delamore IW: The clinical usefulness of C-reactive protein measurements. Br J Haemarol63:411-414, 1986. 23. Lembo RM: Neonatal sepsis screen (letter). Pediatr Infect Dis J 7:77, 1988. 24. Misra PK, Kumar R , Malik GK, Agarwal SK, Mehra P: C-reactive protein in early detection of neonatal infection. Indfedicrrr24: 1039- 104I , 1987. 25. Ramen Y, Artal R: C-reactive protein in pregnancy and in the postpartum period. Am J Obstet Gynecol 151:380-383, 1985. 26. Fisk NM, Fysh JW: C-reactive protein as a marker for infection (letter). Acta Ohstet Gynecol Scand 67: 189, 1988. 27. Gray BM, Simmons D, Mason H, Barnum S, Volanakis J: Quantitative levels of C-reactive protein in cerebrospinal fluid in patients with bacterial meningitis andotherconditions. JPediarr 108( 1):665-670, 1986. 28. Sindic CJM, Collet-Cassart D, Depre A, Laterre ED, Masson PL: C-reactive protein in serum and cerebrospinal fluid in various neurological disorders. J Neurol Sci 63:339-44, 1984. 29. De Beer FC, Kirstin GF, Gie RP, Beyers N, Strachan AF: Value of C-reactive protein measurement in tuberculosis, bacterial and viral meningitis. Arch Dis Child 59:653-656, 1984. 30. Vanprapar N, Chavalittamrong B, Sittapiroj C: Cerebrospinal fluid C-reactive protein. J Med Assoc Thai 7 0 5 19-522, 1987. 31. Abramson JS, Hampton D, Babu S, Wasilauskas BL, Marcon MJ: The use of C-reactive protein from cerebrospinal fluid for differentiatingmeningitis from other central nervous system diseases. J Infect Dis 15 12354-858, 1985. 32. Petola HO, C-reactive protein for rapid monitoring of infections of the central nervous system. Lancet 1 :980-983, 1982. 33. Hirschberg H, Bosnes V: C-reactive protein levels in the differential diagnosis of brain abcesses. J Neiirosurg 67:358-360, 1987.
34. Terada K, Hayashi G , Hokama Y: C-reactive protein and 6-ketoprostaglandin F,* in patients with gynecologic cancer. Gynecol Oncol (in press). 35. DeBeer FC, Hind CRK, Fox KM, Allan RM, Maseri A. Pepys MB: Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 47:239-243, 1982. 36. Pietila K, Harmoinen A, Poyhonen L, Koskinen M, Heikkila J , Ruosteenoja R: Intravenous steptokinase treatment and serum C-reactive protein in patients with acute myocardial infarction. Br Heart J 58:22s-229, 1987. 37. Karma Pq Sipla M, Koskela M, Heikki P C-reactive protein in acute otitis media. Acta Otolaryngol 103:395-399, 1987. 38. Komoroski EM, VanHare G, Shurin PA, et al: Quantitative measurement of C-reactive protein in acute otitis media. J Pediatr 111:81-84, 1987. 39. Boralessa H, DeBeer FC, Manchie A, Whitwam JG, Pepys MB: C-reactive protein in patients undergoing cardiac surgery. Anaesthesia 41: 11-15. 1986. 40. Ghoneim ATM, McGoIdrick J . Ionescu MI: Serial C-reactive protein measurements in infective complications following cardiac operation: Evaluation and use in monitoring response to therapy. Ann Thorac Surg 34: 166- 175, 1982. 41. Miholic J, Hiertz H, Hudec M, Laczkovics A, Domanig E: Fever leukocytosis and infection after open heart surgery. A log-linear regression analysis of 115 cases. Thorac Cardiovasc Surg 32:45-48, 1984. 42. Verkkala K, Voltonen V, Jarvinen A, Tolppanem EM: Fever, leukocytosis and C-reactive protein after open heart surgery and their value in the diagnosis of post operative infections. Thorac Cardiovasc Surg 3517842,1987. 43. Shih LY, Wu JJ, Yang DJ: Erythrocyte sedimentation rate and C-reactive protein values in patients with total hip arthroplasty. Clin Orrhop 225:238-246,1987. 44. Chun PXC, Wong L, Paik YK, Siemson AW, Hokama Y: Examination of urine C-reactive protein and Iysozyme in renal homotransplantation. HawaiiMedJ31:262-265, 1972. 45. Bruzzone P, Spanga G, Castagneto M, Nanni G, Castiglioni GC: Temporal patterns of C-reactive protein and other acute phase proteins after kidney transplantations. Transplant Proc 19:37(5):3727-3730. 1987. 46. Cohen DJ, Benvenisty Al, Meyer E, Hardy MA: Serum C-reactive protein concentrations in cyclosponne-treated renal allograft recipients. Tramplantation 45(5):9 19-922, 1988. 47. Saarinen UM. Strandjord SE, Warkentin PI, Cheung NKV, Lazarus HM, Coccia PF: Differentiation of presumed sepsis from acute graft-versushost disease by C-reactive protein and serum total IgE in bone marrow transplant recipients. Transplanration 44(4):540-546, 1987. 48. Dyck RF: C-reactive protein: A better indicator of complications other than acute rejection in renal allograft recipients? Clin Biochem 21 :359-362, 1988. 49. Rowe IF, Sheldon J , Riches PG, Keat ACS: Comparative studies of serum and synovial fluid C-reactive protein concentrations. Ann Rheum Dis 46:72 1-726, 1987. 50. Hessian PA, Palmer DG:The presence and possible significance of C-reactive protein in rheumatoid inflammation. J Rheumarol 12:871-875, 1985. 5 1 . Larsen A: The relation of radiographic changes to serum acute phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis. Scand J Rheumarol 17:123- 129, 1988. 52. Sanders KM, Hertzman A, Escobar MR, Littman BH: Correlation of immunoglobin and C-reactive protein levels in ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 46:273-276, 1987. 53. Lee FY, Lee SD, Tsai YT, Wu JC, Lai KH, Lo KJ: Serum C-reactive protein as a serum marker for the diagnosis of hepatocellular carcinoma. Cancer 63:1567-1571, 1989. 54. Basso D, Fabris C. Meani A, et a]: C-reactive protein in pancreatic cancer and chronic pancreatitis. Ann CIin Res 20:414-416, 1988.
C-Reactive Protein Applications 55. Maasilta P, Kostiala AAI: Serum levels of C-reactive protein in patients with pulmonary tuberculosis and malignant tumors of the chest. Infection l7(l):l3-l5, 1989. 56. McCartney AC, Orange GV, Pringle SD, Wills G, Reece IJ: Serum C-reactive protein in infectiveendocarditis.JClinPuf/zol41:44-48, 1988. 57. Hellgren U, Julander I: Are white blood cell count, platelet count, erythrocyte sedimentation rate and C-reactive protein useful In the diagnosis of septicaemia and endocarditis?Scand JInfectDis 18:487-488, 1986. 58. Morton RE, Kennedy CR: C-reactive protein concentration in cystic fibrosis. Arch Dis Child 63:958-960, 1988. 59. Glass S, Hayward C, Gova JRW: Serum C-reactive protein in assessment of pulmonary exacerbations and antimicrobial therapy in cystic fibrosis. JPediatr 113(1):76-79, 1988. 60. Puolakkainen P, Valtonen V, Paananen A, Schroder T: C-reactive protein and serum phospholipase A2 in the assessment of the seventy of acute pancreatitis. Gut 764-771, 1987. 61. Heads CWA, Shenkin A, Imrie CW: C-reactive protein, antiproteases and complement factors as objective markers of severity in acute pancreatitis. BrJSurg 76:177-181, 1989.
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62. Teerenhovi 0, Nordback I: C-reactive protein and pancreatic necrosis in acute necrotising pancreatitis. Ann Chir Gynaeco177:61-62, 1988. 63. Boirivany M, Leone M , Tariciotti D, Fais S , Squarcia 0, Pallone F: The clinical significance of serum C-reactive protein levels in Chron’s discase. Results of a prospective longitudinal study. J Clin Gastroenterol 10(4):401-405, 1988. 64. Prantera C, Davoli M, Lorenzetti R, et al: Clinical and laboratory indicators of extent of ulcerative colitis. Serum C-reactive protein helps most. J Clin Gustroenferol 10(1):41-45, 1988. 65. Kress HG, Gehrsitz P, Elert 0:Predictive value of skin testing, neutrophi1 migration and C-reactive protein for postoperative infections in cardiopulmonary bypass patients. Acfa Anaesthesiol Scand 3 1 :397-404, 1987. 66. Katz PR, Gutman SI, Richman G , Karuza J , Bartholomew WR, Baum J: EIrythrocyte sedimentation rate and C-reactive protein compared in the elderly. Clin Chem 35(3):466-468, 1989. 67. Deodhar SD, Valenzuela R: C-reactive protein: New findings and specific applications. Lab Man 19(6):47, 1981. 68. Singer JI, Buchino JJ, Chabali R: Selected laboratory in pediatric emergency care. Emerg Med Clin North Am 4:371-396, 1986.
Potential Clinical Applications of C-Reactive Protein J.M. Okamura, J.M. Miyagi, K. Terada, and Y. Hokama John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu, Hawaii This article reviews the clinical applications of C-reactiveprotein (CRP).This acute-phase protein is a distinct and sensitive marker for inflammation and tissue injury. It is a simple, fast, and relatively inexpensive latex aggluti-
Key words:
Acute-phaseprotein, CRP, inflammation,injury, diagnostic screening, serial testing
INTRODUCTION C-reactive protein (CRP) was first detected in 1930 as a marker for pneumococcal pneumonia (1). It was later shown that, in the presence of calcium ions, this protein would complex with pneumoccal C-polysacchride, and thus the term C-reactive protein was derived (2). CRP has since been demonstrated in a multitude of disease states, the nonspecific hallmarks of which are inflammation and tissue injury. Thus, CRP is considered one of the acute-phase proteins, which includes other serum proteins and glycoproteins that increase during an acute inflammatory episode (3,4). CRP is synthesized by hepatocytes. It has been detected in serum, CSF, and synovial, amniotic, pleural, ascitic, and blister fluids (5). It does not, however, cross the placental membrane (6,7). It is present in healthy individuals, with normal values progressively increasing with age (8,9). CRP has been shown to be elevated within hours of disease onset (10). It increases exponentially with a doubling time of 8.2 hours ( 1 1). It is also rapidly cleared, with a half-life of approximately 6 hr (1 2,13). Although CRP has been evaluated by a number of techniques, most clinical laboratories utilize the latex agglutination test. While this test may lack sensitivity, it is relatively inexpensive and can provide rapid results (14,15). Another commonly used test for CRP determination is the automated laser nephelometer. Once the patient’s serum is obtained, no further steps are required prior to running the test on the nephelometer. The turnaround time in a routine laboratory is about 4 hr, and the test costs approximately $31 sample. Although not commonly found in clinical laboratories, this test is both inexpensive and clinically feasible (16). CRP may increase as much as 2,000-fold in certain diseases, which suggests a significant function; however, CRP’s definitive effects have been elusive. It has been suggested that CRP may function as an opsonin (5,17), CRP has been shown to bind to various bacteria and tissue membranes and to enhance phagocytosis. It also has the ability to activate the classical complement pathway, with subsequent binding and solubili0 1990 Wiley-Liss, Inc.
nation test. The aspects of CRP reviewed include diagnostic support, serial measurements to evaluate disease course and therapeutic response, and screening studies.
zation of DNA (5,18). In addition, various other immune system functions have been also associated with CRP during acute inflammation (5).
CRP VERSUS OTHER INFLAMMATORY FACTORS CRP levels in relation to other inflammatory factors have been extensively examined. The best correlation appears to be between CRP, polymorphonuclear cells, alpha-glycoprotein, and the erythrocyte sedimentation rate (ESR). In comparison with the ESR, CRP appears earlier following onset of disease; returns to normal values earlier; has greater sensitivity; has an extended time limit for the sample to be tested (the blood sample for ESR must be tested within 2 hr after blood is drawn); and is not affected by lowered red blood cell counts, changes in serum protein concentrations, or immunologic status (5,19,20). Thus, although infrequently utilized, CRP should be seriously considered as an alternative or complement to the various other more traditional tests.
CLINICAL ASPECTS OF CRP The clinical usefulness of CRP lies in its ability to reveal early inflammation and tissue injury when other clinical parameters are equivocal. There are three general applications of CRP analysis. First, it can be used as a diagnostic support tool. Second, serial measurements make it possible to follow exacerbations, complications, and/or efficacy of treatment. Third, the CRP test can be used as a screening tool.
Diagnostic Support Diagnostically, CRP is useful in differentiating between bacterial and viral infections, as the former tend toward invasive
Received December 26, 1989; accepted January 2, 1990. Addreas reprint requests to Y. Hokama, Ph.D., Department of Pathology, JABSM, University of Hawaii, Manoa, Honolulu, HI 96822.
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properties that result in inflammation and injury with a subsequent CRP elevation not seen in the latter. For example, when a child presents with a fever requiring a sepsis evaluation, the diagnostic blood culture requires 48 hr and may prove falsely negative. In such cases, studies have shown that CRP is a sensitive and rapidly reacting index in bacteremic infections. The sensitivity approaches 99%- 100%.False-negative results may be due to skin contamination, or may possibly represent a small fraction of cases of real septicemia in which CRP has not had time to increase. However, CRP is not specific. The reason CRP may increase in some viral infections is not fully understood, but such increases may partially be explained by a secondary bacterial infection. Nevertheless, the increased CRP levels with some viral infections emphasize the need to pay more attention to a single unincreased value than an increased CRP value. It has been concluded that, if the history of illness is at least 12 hr and two or more CRP values (taken a few hours apart) are negative, invasive bacterial disease is very unlikely (20). The only exception is in neonates. During the first month of life, CRP is not totally reliable, although it is still useful because CRP is better than other nonspecific laboratory tests (20,21). In adults, CRP appears to be the most sensitive of plasma proteins as an indicator of systemic bacterial infection (22). Studies have shown that CRP sensitivity can be increased by the use of a four-part sepsis screen (white blood cell count, immatureltotal neutrophil ratio [I/T ratio], CRP level, and ESR), which has produced a negative predictive value of loo%, compared with CRP alone at 99%; this small improvement may be significant to clinicians who do not want to miss even a single case (23). As CRP is not transferred across the placenta, a positive CRP value detected within the first few hours of life in an infant whose mother has presented with prolonged rupture of amniotic membranes (PROM) and/or amnionitis can be regarded as a marker for neonatal bacterial infection (6,24,25). After the first day of life, however, a positive CRP may also be caused by various other conditions. In contrast, elevated maternal CRP values before delivery predict infectious morbidity in only 8%-29% of patients, and up to 18% of patients with serious infections may be misdiagnosed as having normal CRP values before delivery (15,26). CRP is beneficial in differentiating bacterial from viral meningitis (27-30). CRP is highly sensitive. False-positive results, however, are not of overwhelming concern, since other bacterial infections may be equally life-threatening and also require prompt antibiotic therapy. The difficulty comes with the occasional false-negative result, which could lead to withholding of antibiotics from a patient with bacterial meningitis. Therefore, the clinician must evaluate the patient as a whole and recognize the inherent limitations of a test related to the inflammatory reaction of the host (27,31). Both serum and CSF CRP values are of diagnostic significance. However, some studies suggest that the assay of CSF is less discriminatory due to local consumption of CRP, resulting in levels that may
be misleadingly low (28,32). Regardless, the CRP test is more rapid than any other laboratory test available for detecting bacterial meningitis, except for the Gram stain; however, CRP is much more sensitive (97%) than the Gram stain (80%). When computerized tomography (CT) scans are equivocal, CRP may be useful in differentiating between a tumor and an abcess. A significant rise in CRP levels has been observed in most cases of bacterial brain abcesses; the most pronounced rise was recorded early in the course of the disease (cerebritis) before a well-defined abcess membrane was formed (33). Nonmetastatic tumors, on the other hand, will show little if any elevation of CRP (34). The relationship between the rise in creatinine kinase-MB fraction (CK-MB) and CRP in patients experiencing myocardial infarction (MI) has been studied (35,36). The results show that a rise in CRP in cases of chest pain without a rise in CK-MB is strongly suggestive of a noninfarctive or noncardiac lesion. In addition, DeBeer et al. (35) reported that, because CRP levels peaked at a mean time of 50 hr after the onset of chest pain following an MI, in comparison with 15 hr to peak CK-MB, CRP may be useful in cases where infarction is only suspected when CK-MB values may have returned to normal. With respect to the above findings, deliberate care must be taken to rule out other possible sources of inflammation or injury such as urinary tract infection, respiratory tract infection, otitis media (37,38), and other diseases that may also produce a elevated CRP level.
Serial Measurements Serial measurements of CRP may provide valuable information regarding the course of a disease with respect to exacerbations, complications, and the efficacy of treatment. The typical CRP elevation pattern is a rapid rise within hours of disease onset. CRP then remains elevated as long as the disease state remains. An uneventful recovery is heralded by levels that fall rapidly. A persistent elevation or a re-elevation is a warning sign indicating that further investigation may be necessary. The value of serial CRP determinations in postoperative patients who have undergone cardiac surgery is well-established (39-41). Studies have demonstrated the usefulness of CRP in predicting postoperative infectious complications before the onset of clinical symptoms. CRP has also been shown to be of greater diagnostic value for infection than a rise in white blood cells or temperature in open-heart surgery patients during their post operative course (42). In patients undergoing total hip arthroplasty procedures, CRP was found to be useful post-operatively in differentiating between septic loosening of the hip, which significantly elevated CRP levels, and mechanical loosening, in which CRP remained normal (43). The value of CRP determinations in transplant recipients has also been investigated (44-48). In bone marrow transplant recipients, low CRP coupled with high IgE levels can
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differentiate graft-versus-host disease from sepsis, which presents with high CRP and low IgE levels (47). Quantitative CRP measurements are also useful. Renal allograft recipients with CRP values exceeding 60 ng/ml are much more likely to have a serious complication other than acute rejection alone (48). In the field of rheumatology, studies have been done comparing serum and synovial fluid CRP concentrations. These have shown the possibility that, as in meningitic CSF, CRP is either selectively bound in synovium or specifically consumed in a synovial fluid, which may play a role in rheumatoid inflammation (49,50). Serum CRP has been shown to correlate significantly with radiographic changes in rheumatoid arthritis (51); it also has a significant positive correlation with rheumatoid arthritic disease as a whole (49-52). CRP determinations also may play a valuable role in the field of oncology (34,53-55). The combination of serum alphafetoprotein and CRP levels was shown to be effective in differentiating patients with hepatocellular carcinoma from those with benign liver diseases. CRP levels were also found to decrease after successful tumor resection (53). Quantitative CRP levels have been found to increase with tumor extent in patients with pancreatic cancer and thus may help in estimating progression of a tumor (54). Serial measurements may be used to monitor the course of practically any disease that possesses an inflammatory component. Examples include endocarditis, where studues have shown that serial CRP measurements are of more value than estimations of serum bacterial titer both in prognosis and in predicting continuing infection in infective endocarditis (56,57). In cystic fibrosis, the CRP concentration was highly correlated with the Shwachman clinical evaluation score, forced vital capacity as a percentage of the predicted value, and the Chrispin-Norman x-ray score. A rising CRP appears to be a simple objective index of worsening clinical condition, whereas white cell count and ESR were not found to be useful. Serum concentrations may be used as early markers of deterioration in patients with cystic fibrosis who are not yet severely affected; in the absence of pulmonary excerbation, CF is not associated with raised CRP values (58,59). CRP has been shown to be a useful aid in assessing the severity of acute pancreatitis (60-62). An increase in CRP has been shown to discriminate between mild pancreatitis and hemorrhagic pancreatritis, with an increase to greater than 250 mg/L being highly suggestive of extensive pancreatic necrosis. In inflammatory bowel diseases, CRP has been shown to be valuable in determining the extent of disease in monitoring the response to treatment, in predicting outcome, and in defining prognostic subgroups of patients (63,641.
CRP Screening The use of CRP as a screening test has been investigated, but studies to assess the value of such tests have met with
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limited success (5,39). One study has shown preoperative screening CRP measurements in cardiac surgery patients to be predictive of postoperative infectious complications (39). However, these observations have been challenged (65). The CRP test has been proposed as a screen for blood donors (5), but further investigation is necessary. CRP screening has not been shown to adequately assess ongoing active or chronic disease in the elderly (65). This is possibly due to both the unpredictability of CRP with advancing age and the greater prevalence of inflammatory states in the elderly population. Thus, the role of CRP in screening for occult inflammation, general health status, and blood donors has so far proven minimal and requiring further study.
CONCLUSIONS In summary, while CRP is a frequently overlooked test, it has been shown to be an invaluable tool in diagnostic support and in aiding the evaluation of disease course and therapeutic response. In addition, the simplicity, speed, and relative inexpensiveness of the test make it clinically feasible and practical. CRP’s properties as a distinct and sensitive marker for inflammation and tissue injury make its use in diagnosis, prognosis, course, treatment efficacy, and screening virtually limitless. The future use of CRP as a routine laboratory test in patient evaluation appears imminent, and knowledge of its applications will likely become a necessity for modem-day practitioners in all fields of medicine (67,68).
ACKNOWLEDGMENTS Supported in part by the Hokama-Yagawa Memorial Fund, UHF.
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