Serial C-reactive Protein Measurements in Infective Complications Following Cardiac Operation: Evaluation and Use in Monitoring Response to Therapy

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1 Serial C-reactive Protein Measurements in Infective Complications Following Cardiac Operation: Evaluation and Use in Monitoring Response to Therapy ~. Adeeb T. M. Ghoneim, M.R.C.Path., John McGoldrick, F.I.M.L.T., and Marian I. Ionescu, M.D. ABSTRACT Serum C-reactive protein (CRP) was studied serially in 100 patients who underwent cardiac operation and in another 17 patients in whom serious infections including prosthetic valve endocarditis developed in the early postoperative period. Eleven patients with late onset of prosthetic valve endocarditis and infective endocarditis were also investigated. The assay method used was radial immunodiffusion. Patients without postoperative infective complications showed a rapid increase in CRP levels, which reached a peak within 72 hours after operation followed by a progressive decline. The differences between the CRP levels in infected and uninfected patients were significant (p < 0.01). Serial measurements were of prognostic value in evaluating the response to chemotherapy and in predicting the outcome of the disease. Postoperative infections are among the most serious complications following cardiac operations, and early diagnosis and treatment may be lifesaving. Various nonspecific laboratory tests, such as white blood cell count and erythrocyte sedimentation rate (ESR), are used as aids for the detection and follow-up of infection. However, they often show wide variation in the complex postoperative conditions where bleeding, changes in plasma proteins and lipids, and the presence of hematoma and necrotic material may result in elevated white blood cell count and ESR even in the absence of infection. Furthermore, in certain infections the leukocytic response may be depressed and re- From the Department of Microbiology, The University of Leeds, and the Cardiothoracic Unit, The General Infirmary at Leeds, Leeds, England. Accepted for publication Oct 8, Address reprint requests to Mr. Ionescu, Department of Cardiothoracic Surgery, Leeds General Infirmary, Leeds LS1 3EX, England. liance on white blood cell count may be misleading [l]. Studies on acute-phase protein levels have shown the C-reactive protein (CRP) to rise more rapidly than the other proteins following inflammation and tissue damage. The CRP levels also return to the normal levels of less than 20 mgll more rapidly, permitting easier detection of any secondary response. Previous studies have shown that the greatest increase in all acute-phase proteins was observed with bacterial infections, while viral infections had slightly elevated CRP levels [2]. The CRP level can be measured accurately, and its rapid rate of change was thought to make it a more sensitive immediate test than others as a marker of infection. Although such a rise is a nonspecific one, its use in monitoring neonatal infections [3], infections in patients with hematological malignancies [4], and postoperative complications [5] has been suggested. This report describes the time course of CRP levels in patients following uncomplicated open-heart operations and its behavior in patients in whom serious infections developed in the early postoperative period. The value of CRP levels in monitoring the progress of infection and response to therapy is discussed. Material and Methods Patients Having Cardiac Operation The pattern of postoperative serum CRP response was studied in 100 consecutive patients who underwent various cardiac operations (Table 1). Two milliliters of clotted blood was collected 1 to 5 days prior to operation and then twice weekly following the operation. From 50 patients four to ten samples were collected, while from the other 50 patients only two to four samples. Serial measurement of the ESR was performed concurrently by The Society of Thoracic Surgeons

2 ~~ 167 Ghoneim et al: C-reactive Protein following Cardiac Operation Table 1. Cardiac Operations in 100 Consecutive Patients Investigated for Serum C-reactive Protein Levels Type of Operation Aortic valve replacement 26 Mitral valve replacement 23 Mitral and aortic valve replacement 21 Aortocoronary bypass graft 21 Mitral valve replacement and aorto- 6 coronary bypass graft Repair of atrial septal defect 3 No. of Patients Patients with Early Postoperative Complications During the five-year study period, 17 out of 900 patients who underwent cardiac operation experienced major infections in the early postoperative period (onset, less than 3 months after operation). Ten patients had serious wound infection, and in 5 of them the infection was accompanied or followed by septicemia and endocarditis; 2 other patients had endocarditis with no wound infection. The causative organisms were Staphylococcus aureus (8 patients), Pseudomonas aeruginosa (1 patient), Klebsiella aerogenes (1 patient), Staphylococcus epidermidis (1 patient), and one infection caused by Streptococcus faecalis. Peritonitis developed in 3 patients during peritoneal dialysis for acute renal failure. The causative agents were P. aeruginosa (l), Klebsiella oxytoca (l), and Acinetobacter calcoacaticus var. anitratus (1). Two patients had pneumonia caused by P. aeruginosa. Clinical criteria for diagnosis of infection included pyrexia, toxemia, the presence of a discharging wound, leukocytosis, and isolation of the organism from the wound, sputum, peritoneal dialysis fluid, or blood cultures. In patients with bacteriologically documented infections, samples of blood for CRP assays were collected daily or at least twice weekly during treatment until discharge from the hospital. Patients with Infective Endocarditis During the same five years, 4 patients experienced prosthetic valve endocarditis late (more than 3 months) postoperatively. It was caused by S. epidermidis (l), Streptococcus faecalis (l), and Streptococcus viridans (1). In the fourth patient, endocarditis caused by S. aureus developed following infection of the intravenous catheter site used for the continuous infusion of heparin. In 7 patients who had no previous cardiac operation, endocarditis developed on the native valve. The causative organisms were Streptococcus viridans (4), P-hemolytic streptococcus of group C (2), and S. aureus (1) following insertion of an endocardia1 pacemaker system. Serum C-reactive Protein The CRP levels were measured by single radial immunodiffusion, using the method of Mancini and colleagues [6]. Human CRP antisera and standards were obtained from Seward Immunostics in London. Patient s sera were used neat and in 1/10 dilution in 0.9% weight per volume of sodium chloride. The levels were calculated from a standard curve, prepared for each new batch of antiserum. Results The pattern of the ESR and CRP responses in the uninfected patients postoperatively is presented in Figures 1 and 2. The preoperative CRP levels were all less than 20 mg/l. From the first few hours after operation, the CRP levels started to rise until the peak was reached by the third day (mean, 420 mg/l). This was followed by progressive decline until levels of less than 30 mg/l were reached by the third postoperative week. Because of the high CRP levels in the first week produced as a reaction to surgical trauma, it was possible to detect elevations suggestive of infection from the second week onward when persistent high levels were consistent with infective complications (Fig 3). In this series, levels of 200 mg/l or higher in the second postoperative week or of 100 mg/l or above during the third postoperative week were always associated with infection. The levels shown in Figure 3 represent those obtained at the time the infection was first suspected or diagnosed. The clinical details and CRP levels in patients in whom infection developed are presented in Table 2. The difference between the CRP levels in the infected patients and in those without infection was statistically

3 168 The Annals of Thoracic Surgery Vol 34 No 2 August 1982 < I I20 - loo - : 80- Q: I9 T I Ronge Medion I 0 I II I I7 18 I9 to21 hy,days befom-of Operation- Oays after 0 Fig 1. Erythrocyte sedimentation rate (ESR) levels in random samples collected from 100 patients following cardiac operation. The data represent median levels and range in patients without infection. 1 Medion I Ronge I I I l l l l l l l l l l l l l I l l l l l l l i 2 I 0 I DII I I hy *OOP before 'of Operation- Oays after * Fig 2. Serum C-reactive protein (CRP) levels in random samples collected from 100 patients following cardiac operation. The data represent median levels and range in patients without infection.

4 169 Ghoneim et al: C-reactive Protein following Cardiac Operation roo - 0 Endocorditis 0 Wound infection 0 Peritonitis 0 Pneumonia \ P, 400- E Q Qr 300- c, loo ~ B I O P W l M ~ 2 4 ~ d ~ Y ~ ~ ~ O DPY Oays before 4 of'0perat ion Oays after c Fig 3. Serum C-reactive protein (CW) levels in patients with early postoperative infection. The shadowed zone (a) represents the normal postoperative CRP response. significant (p < 0.01; t test). The CRP levels from a selected number of patients are shown in Figures 4, 5, and 6. Illustrative Case Reports A 48-year-old man underwent mitral and tricuspid valve replacement in November, The first postoperative week was uneventful (see Fig 4). On day 7 the discharge from a purulent wound was sent for culture, and s. UUreus was isolated. Blood cultures were sterile, and the CRP level obtained on the tenth postoperative day was 450 mg/l. Because the organism was partially resistant to cloxacillin, treatment with gentamicin and fusidic acid was started. After initial response, the CRP levels rose again and remained at a high level (approximately 300 mgll) during the following 14 days until the patient died 28 days after operation with signs of septicemia. A 52-year-old man underwent aortocoronary bypass graft. The CRP response during the first 10 days after operation was normal. On day 13, he became pyrexial and the diagnosis of sternal wound infection caused by S. aureus was confirmed by the isolation of the organism from wound discharge. The CRP level was 335 and rose to 675 mg/l during the following 48 hours. Treatment with cloxacillin and Fucidine (sodium fusidate) was started and continued for 2 weeks. During that period the patient's condition improved, and the wound discharge became sterile. Serial measurements of the CRP levels showed low values (20 mg/l) for 8 days. However, after the treatment was discontinued the patient had a relapse and further studies showed a secondary CRP response, which accompanied a further isolation of S. aureus from the wound. Hence, the wound was surgically debrided and treatment was given with gentamicin and cloxacillin for 2 weeks, followed by cloxacillin for 4 weeks (see Fig 5). Retrospective analysis suggests that the 2-week treatment of deep sternal wound infection was inadequate and that prolonged therapy might have been needed. In addition, the use of Fucidine in spite of the expected high bone level may have been followed by the emergence of few Fucidine-resistant mutants. It is possible that during the period when the CRP levels were low, the infection was dormant with few viable bacterial cells. The use of CRP levels after discontinuation of therapy gave a warning of the reactivation of the infective process, therefore more aggressive therapy was used for the second infection.

5 170 The Annals of Thoracic Surgery Vol 34 No 2 August 1982 Table 2. Clinical Details of Patients with Postoperative Infective Complications Infection/ CRP Levels at Patient No., Organism1 Beginningduring Chemotherapy Age (yr), Sex Day Postop Infection (days) Outcome 1. 45, M Endocarditisl K. aerogenesll , 179, , F Endocarditisl , 178, 76, 198, S. aureusll4 225,235, , M Endocarditisl S. epiderrnidis I , , M Wound infectionl S. aureusll , 98, 80, 60, , F Wound infection , 76, 32, 26 + septicemia1 S. aureusll , M Peritonitisl , 365, 165,335, K. oxytocal9 215,380, , F Peritonitisl Acinetobacter sp , , M Wound infectionl , 495, 320, 460, S. aureusll , F , M Peritonitisl Wound infectionl , , 210, 330, 220, P. aeruginosal S. aureusll0 255,290, , M , M , M Wound infection/ Wound infectionl Wound infectionl , 167, 164, 89, 73, , 127, 93, 63, 61, , 95, 80, 45, S. aureusll3 S. aureusll3 P. aeruginosal 43,20 40, , F Wound infectionl , 125,90, 60,45, 21 S. faecalis118 30, M Wound infection/ , 530, 190, 155, 14 S. aureusll3 135,17 Wound infection/ S. aureusl34 (relapse) , 160, 100,30, , F Pneumonial , 310, P. aeruginosal F Pneumonial , 255, 305, 275, 7 P. aeruginosal Pseudomonas aeruginosa is an opportunistic organism responsible for infection in compromised patients, especially those who are treated for many days with antibiotics in the intensive care unit. Figure 6 shows the CRP response in 3 patients with P. aeruginosa infection. Patient 1 had P. aeruginosa pneumonia. The infection was treated with gentamicin. However, this treatment was unsuccessful and the patient died 16 days after operation. The CRP response showed persistently high and rising levels. Patient 2 had renal failure in the early postoperative period. Following 4 days of peritoneal dialysis, peritonitis due to P.

6 171 Ghoneim et al: C-reactive Protein following Cardiac Operation a T 400 i? Q 300 9: c, I I I 1 I I I I I X) Days after L Fig 4. Serial measurements of serum C-reactive protein (CRP) from a patient with Staphylococcus aureus sternal wound infection. The patient died on postoperative day 28. The shadowed zone (a) represents the normal postoperative CRP response. - \ & a 200 I t I I I I I I 1 I I I I I I 1 1 I hy *Days kfon --of Operation- Days after I l820zn26~a w Fig 5. Serial measurements of serum C-reactive protein (CRP) from a patient with Staphylococcus aureus sternal wound infection. The shadowed zone (a) represents the normal postoperative CRP response. The two CRP peaks represent two episodes of wound infection.

7 172 The Annals of Thoracic Surgery Vol 34 No 2 August Oays before -of Operation I I I I O I 2 ~ 1 6 l ~ ~ ~ 3 0 ~ ~ ky Days after - Fig 6. Serum C-reactive protein (CRP) response in patients with Pseudomonas aeruginosa infections. Patient 1 had pneumonia, and Patient 2 had peritonitis. Both died of uncontrolled infection. Patient 3 had a sternal wound infection, which was successfully treated. The shadowed zone (a) represents the normal postoperative CRP response. aeruginosa developed, which was followed by septicemia. Treatment of the infection was unsuccessful, and she died on the twenty-second postoperative day. The CRP levels continued to rise, and a peak of 550 mgll was reached just before her death. Patient 3 remained in the intensive care unit for 3 weeks because of complications not related to infection. He needed tracheostomy. The tracheostomy wound became colonized by P. aeruginosa. Later, the sternal wound became infected also. A CRP level of 175 mgll at day 27 was abnormal and was accompanied by the isolation of the organism from the sternal wound. Treatment with tobramycin and ticarcillin was started, and the infection responded well to treatment. The CRP levels in patients in whom early prosthetic valve endocarditis developed, in those with late onset of prosthetic valve endocarditis, and in patients with infective endocarditis on native valves are shown in Figure 7. A B ;I. C. - Fig 7. Serum C-reactive protein (CRP) levels in patients having cardiac operation but no infection (A), patients with late onset of prosthetic valve endocarditis and infective endocarditis (B), and patients with early prosthetic valve endocarditis (C). The levels shown represent serum levels when first tested after the clinical diagnosis of endocarditis had been made, and each measurement represents l patient. In section B, the open circles represent patients with late onset of prosthetic valve endocarditis while the closed circles are those with endocarditis of native valves. Mean and standard deviation are indicated for each group.. -

8 173 Ghoneim et al: C-reactive Protein following Cardiac Operation In early postoperative endocarditis, which almost always was caused by a highly virulent organism and was accompanied by wound infection, the levels, as expected, were higher than in those patients with late onset of prosthetic valve endocarditis. The difference between the CRP level in patients with different types of endocarditis and patients who had a cardiac operation but no infection was statistically significant (p < 0.01; t test). Comment Infection following a cardiac operation is usually a serious complication. Because of the use of prophylactic antibiotics immediately before and for a short period after operation and because time is needed for bacteria to multiply and invade the tissues, early infections may pass undetected. Tests that draw attention to the possible presence of early infection in such patients are of considerable value because they will call for extensive investigation and early diagnosis. Specific tests utilizing circulating antibodies or circulating immune complexes have been suggested for the diagnosis of infective endocarditis. However, these complexes appear in the circulation several days after the onset of septicemia and may persist for a long time [7-91. Detection of the circulating bacterial antigens may be a more sensitive test for bacteremia. However, the polymicrobial nature of the disease and the antigenic variations between different strains of the same species may complicate the test. Trauma, tissue damage, inflammation, and infection are associated with acute-phase phenomenon, which is characterized by the presence of fever, leukocytosis, increase in the ESR, and rapid and relatively nonspecific increase in acute-phase proteins. The proteins that have been identified as acute phase are a group of glycoproteins consisting of alpha, acid glycoprotein, alpha,-antitrypsin, ceruloplasmin, haptoglobulin, fibrinogen, and C-reactive protein. Measurement of these proteins has proved valuable in diagnosing a disease state involving inflammation and tissue damage, and in monitoring the effectiveness of therapy. Previous studies on acute-phase protein levels have shown the CRP to rise more rapidly and dramatically than the other proteins following inflammation and tissue damage and that the levels return to normal much faster. This rapid rate of change of CRP makes it a more sensitive test than other acute-phase protein and nonspecific tests of the ESR or white cell count. In 1957, Rapport and associates [lo] described the pattern of postoperative CRP response in a group of patients who underwent various surgical procedures. Several reports followed this publication [l, 51 and confirmed Rapport s observation. Our results in patients having uncomplicated cardiac surgical operation showed a similar pattern. A level of 30 mg/l was achieved by the third postoperative week. High CRP levels during or after the second postoperative week were associated with clinical infection. The CRP levels did reflect the clinical state of the patient: they failed to decline when complications occurred and, in general, remained high or even increased abruptly as infection progressed. In our group of patients, the only important possible cause of high CRP other than infection is myocardial infarction. In a previous report involving patients who had cardiac disease and received medical treatment, and in whom a major myocardial infarction developed, the CRP levels rose to a very high level, while minor infarction or angina did not produce such a rise [ll]. This possibility should be borne in mind when assessing the importance of a high CRP level in a patient after cardiac operation. However, this complication is an early one and it can be diagnosed easily by electrocardiographic and enzyme changes. The relationship between elevated ESR and the presence of CRP in the serum has been the subject of many reports. Most authors, however, seem to agree that CRP, which rapidly reflects changes of an inflammatory process, is a more sensitive indicator than the ESR [5, 12, 131. Hedlund [13] in 1961 showed that in acute inflammation, the serum CRP rose earlier than the ESR and that the ESR remained elevated considerably longer than the serum CRP. It is unlikely that concentrations of CRP could di-

9 174 The Annals of Thoracic Surgery Vol 34 No 2 August 1982 rectly affect either ESR or plasma viscosity, and it was suggested that quantitation of CRP in addition to measurement of ESR can offer further diagnostic information [14]. In our series, the postoperative ESR (see Fig 1) was so variable and unpredictable that its use as an early marker of infection was precluded. Serial studies of CRP were found to be of greater value in the diagnosis and in the monitoring response to therapy than were single estimations. We currently collect sera for CRP levels whenever blood cultures or other blood tests are required. Although pyrexia occurred with many infections and was associated with a high CRP level, elevated CRP levels occurred also when the temperature was within the normal range. During successful treatment the CRP levels showed a more rapid response than ESR, white blood cell count, or body temperature. On the basis of our findings, we usually undertake an intensive investigation for a focus of infection in any patient with a high CRP level (greater than 100 mgll) in the third postoperative week, even in the absence of pyrexia. We have not noticed low CRP levels in the presence of active bacterial infection. However, in a previous study [15] we reported that 2 patients with transient bacteremia caused by Streptococcus viridans and Streptococcus faecalis had persistently low CRP levels. Rose and colleagues [4] in a study of infection in patients with leukemia found a similar phenomenon with Streptococcus viridans and Staphylococcus albus bacteremia. They postulated that patients with rheumatoid arthritis and perhaps other diseases may behave as poor responders and produce persistently low levels of CRP. Hence, the possibility of a poor response should be considered in the presence of low CRP levels and an otherwise clear evidence of infection. Self-limiting bacterial infections, noninfective inflammation, tissue damage, and virus infections may show an initial high CRP level with a subsequent decline, even without antibiotic treatment. Our results emphasize the importance of serial studies of CRP levels. It is not surprising that in many early studies, a single estimation of CRP using nonquantitative tests was meaningless and led many clinicians to underesti- mate the value of this test. Because the CRP response is nonspecific, it is affected by different bacteria and that makes it a useful screening test for bacterial infections. We used the CRP levels as an aid to monitoring the response to therapy. Within 24 to 48 hours of successful therapy, the CRP levels showed a marked reduction, which was interpreted as an indication that the inflammation was subsiding. The CRP levels may be used to study the optimum duration of therapy in such infections as sternal osteomyelitis, deep wound infections, and endocarditis. The CRP levels may be of value in the diagnosis of peritonitis after peritoneal dialysis, especially when the causative organisms may be difficult to isolate from the dialysis fluid. In conclusion, the present study provides additional evidence to the value of serial CRP measurements in the diagnosis of infection following cardiac operation and in monitoring the response to therapy. We are grateful to Professor E. H. Cooper and to Professor E. Mary Cooper for advice in the preparation of this paper. The study was supported by Grant No , The University of Leeds. References 1. Fischer CL, Gill C, Forrester MG, Nakamura R: Quantitation of acute-phase proteins postoperatively: value in detection and monitoring of complications. Am J Clin Pathol66:840, Powell LJ: C-reactive protein: a review. Am J Med Techno1 45:138, Saxstad J, Nilsson LA, Hanson LA: C-reactive protein in serum from infants as determined with immunodiffusion techniques: 11. Infants with various infections. Acta Paediatr Scand 59:676, Rose PE, Johnson SA, Meakin M, et al: Serial study of C-reactive protein during infection in leukaemia. J Clin Pathol 34:263, Matsushima Y: C-reactive protein in the postoperative patient. Bull Tokyo Med Dent Univ 14:1, Mancini G, Carbonara AO, Heremans JF: Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 2: 235, Bayer AS, Theofilopoulos AN, Tillman DB, et al: Use of circulating immune complex levels in the sero-identification of endocarditis and nonendocarditic septicemias. Am J Med 66:58, Bayer AS, Theofilopoulos AN, Dixon FJ, Guze

10 175 Ghoneim et al: C-reactive Protein following Cardiac Operation LB: Circulating immune complexes in experimental streptococcal endocarditis: a monitor of therapeutic efficacy. J Infect Dis 139:1, Harkiss GD, Brown DL, Evans DB: Longitudinal study of circulating immune complexes in a patient with Staphylococcus allus-induced shunt nephritis. Clin Exp Immunol 37:228, Rapport MM, Schwartz AE, Graf L: C-reactive protein in patients following operation. Ann Surg 145:321, Kushner I, Broder ML, Karp D: Serum C-reactive protein kinetics after acute myocardial infarction. J Clin Invest 61:235, Yokoyama M: Increase of WBC, CRP and BSR following cardiac pacemaker implant. Am Heart J 95:671, Hedlund P: Clinical and experimental studies on C-reactive protein (acute phase protein). Acta Med Scand [Suppl] 361, Abd-El-Fattah M, Scherer R, Rubenstroth-Bauer G: Erythrocyte sedimentation rate and C-reactive protein. Klin Wochenschr 54:169, Ghoneim ATM, Haworth SL, Ionescu MI: Serum C-reactive protein levels in septicaemia and endocarditis, In Bircks W, Ostermyer J, Schulte HD (eds): Cardiovascular Surgery. Berlin, Springer-Verlag, 1981, pp