1Department of Medicine, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland
2Department of Biostatistics, University of Turku, Turku, Finland
3Central Laboratory, Turku University Central Hospital, Turku, Finland
Received 25 November 2004; revised 19 February 2005; accepted 18 March 2005; online publish-ahead-of-print 26 April 2005.
* Corresponding author. Tel: +358 2 3130000; fax: +358 2 3132030. E-mail address: maija.heiro{at}tyks.fi
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Abstract |
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Methods and results C-reactive protein, erythrocyte sedimentation rate (ESR), and white blood cell count (WBC) were measured from admission until week 10 in 129 patients with 134 episodes of IE. Need for cardiac surgery and final outcome were assessed until 3 months from admission. Data were evaluated using extensive statistical analyses. The fall in serum C-reactive protein or WBC was significantly faster when a patient had an uncomplicated recovery than when complications developed or death ensued, but no such behaviour was observed in ESR. None of the 80 patients who had normal C-reactive protein by week 10 died of IE. Moreover, none of the 22 patients who had normal C-reactive protein by week 4 needed cardiac surgery and only two of the 33 patients who had normal C-reactive protein by week 6 needed cardiac surgery, both after successful medical treatment of IE. Of the 87 patients whose WBC normalized within 4 weeks, six died and 15 needed valve surgery.
Conclusion The normalization of C-reactive protein proved to be a good predictor of a favourable late outcome (surgery, death) of IE. Also WBC count proved useful in the assessment of patients with IE, but the value of ESR was negligible.
Key Words: C-reactive protein Erythrocyte sedimentation rate Infective endocarditis White blood cell count
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Introduction |
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The clinical usefulness of serial C-reactive protein measurements in monitoring the response to therapy in patients with septicaemia and bacterial meningitis is well documented.35 A number of other studies610 have focused on the value of C-reactive protein in infective endocarditis (IE). Most of these studies have involved a relatively small number of patients and limited or no statistics.68 Moreover, in some of them, only C-reactive protein values on admission have been examined.10
In this study, we retrospectively reviewed C-reactive protein, ESR, and WBC counts in patients treated for IE in a Finnish university hospital and used extensive statistical analyses to evaluate the clinical usefulness of these laboratory parameters in the assessment of disease severity and outcome of IE.
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Methods |
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The hospital records of these patients were retrospectively reviewed to collect data on age, sex, blood culture results, involved valves, echocardiographic findings, duration of symptoms of IE, and administration of peroral antimicrobial therapy before admission. Clinical events including neurological complications, peripheral emboli, valve surgery, and mortality were recorded from the onset of symptoms to 3 months after admission to hospital.
The course of IE was defined as complicated when the patient had neurological manifestations or peripheral emboli or needed cardiac surgery, or died within 3 months.
Laboratory parameters
Serum C-reactive protein and ESR values and WBC counts on admission and during the following 10 weeks were registered. The C-reactive protein values were examined on admission, several times during the first in-hospital week and, subsequently, at least two times a week. We included in the statistical analyses the values on admission, the peak values during the treatment, and the last values measured during the 1st, 2nd, 3rd, 4th, 6th, 8th, and 10th week. C-reactive protein concentration of <10 mg/L was considered normal. Reference values for ESR were 20 mm/h for men and
30 mm/h for women. Reference values for WBC counts were 4.010.0x109/L.
Statistical analyses
The differences between groups in the mean values of the C-reactive protein, ESR, and WBC peak recordings and the recordings on admission were statistically tested with the one-way analysis of variance (ANOVA, which is equal to the t-test in a special case of comparison of only two groups). Tukey's multiple comparison correction technique was applied in post hoc comparisons of ANOVA.
Overall differences in the mean values and the changes in the mean values during the follow-up were tested using the analysis of variance of repeated measurements (RANOVA), which is a suitable analysis technique for correlated observations from same subjects.14 The repeated measures ANOVA was carried out using the model in which a complicated course of IE, surgery, or death was a fixed grouping factor and the time in full weeks (010) was a fixed within subject factor. The covariance matrix of repeated measurements was assumed to be unstructured (which led to the best fit). The normality of residuals was evaluated graphically and with ShapiroWilk's test. The normality assumption was found to fit in original scales for C-reactive protein and ESR and, after logarithmic transformation, for WBC. Three effects (group effect, time effect, and interaction between group and time) were tested. Association of the C-reactive protein, ESR, and WBC values at different time points with the outcome of the treatment or complications were analysed using logistic regression analysis. With this technique, it was possible to study the trends in associations and also to evaluate the ability to make predictions using some cut-off points in the laboratory tests. The assumption of linearity in the logistic models was tested with HosmerLemeshow lack of fit test. The results of logistic regression analysis were quantified using odds ratios (OR) with 95% CI. The overall accuracy of the laboratory tests in prediction of death was quantified with c-index, which is the area under receiver operating characteristic (ROC) curve. The ROC curve was also used in the search of the cut-off points for prediction of death.15 The difference in mortality or need for surgery between patients with normalized and elevated laboratory recordings after different treatment periods was tested using Fishers's exact test. The per cent of episodes with elevated C-reactive protein, ESR, and WBC counts during the follow-up in different study groups were estimated with the KaplanMeier curves. The difference between curves was tested with log-rank test. These techniques are well known in survival analysis (or event history analysis more generally).16 In all tests, P-values <0.05 were considered significant. All tests were two-sided. The statistical computations were performed with SAS system for Windows, release 8.2/2001.
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Results |
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C-reactive protein
C-reactive protein on admission and peak C-reactive protein
C-reactive protein was elevated in all 134 episodes; mean values related to various patient characteristics are depicted in Table 2. C-reactive protein was highest in episodes caused by Streptococcus pneumoniae followed by those caused by Staphylococcus aureus and lowest in infections caused by viridans streptococci. Native valve IE was associated with significantly higher C-reactive protein values than prosthetic valve IE.
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In the trend analysis of association, it was found that on week 2 after admission, an increment of 50 mg/L (SD of C-reactive protein, 54 mg/L) of C-reactive protein was associated with a 1.5-fold odds for death (OR=1.5, 95% CI, 0.972.3; P=0.068). In a similar analysis of the C-reactive protein values on week 4, corresponding to every increment of 50 mg/L, the odds for death was over two-fold (OR=2.3, 95% CI, 1.24.4; P=0.009).
Normalization of C-reactive protein during treatment
C-reactive protein normalized in 87 episodes, but later rose again because of intractable infection in seven episodes. In these cases, the first normalization was not included in the statistical analyses. The proportion of C-reactive protein values that remained elevated during treatment was significantly higher in patients with a complicated course of IE than in those with an uncomplicated course (Figure 1A), and in those who needed surgery than in those who were treated medically (Figure 2A). C-reactive protein remained elevated in all of the episodes with a fatal outcome (Figure 3A).
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Erythrocyte sedimentation rate
ESR on admission and peak ESR
ESR values were available in 129 disease episodes. ESR was normal on admission in 14 episodes and remained normal throughout the illness in five episodes. ESR was significantly higher in native valve disease than in prosthetic valve disease (Table 2).
Changes of ESR during treatment
No differences (RANOVA) in ESR values were observed between patients with a complicated or an uncomplicated course of IE, those who needed surgery or were treated only medically, or those who died or survived. In the trend analysis of association, it was found that an increment in ESR on weeks 2 or 4 was not significantly associated with an increase in odds for death.
Normalization of ESR during treatment
ESR normalized in 46 episodes, but increased later because of intractable infection in five cases. In these cases, the first normalization was not included in the statistical analyses. No significant differences were observed in the proportions of episodes with elevated ESRs between patients who had a complicated or an uncomplicated course of IE (Figure 1B), those who needed surgery or were treated only medically (Figure 2B), or those who died or survived (Figure 3B). The normalization of ESR was not associated with the outcome of IE during the follow-up.
Association between ESR and cardiac surgery or death
At the time of surgery, ESR was normal in eight patients, elevated in 33 patients, and not determined in 12 patients. The preoperative ESR values were not different in patients who had positive or negative bacterial cultures on the valve tissue removed at surgery. Five (18.5%) of the 27 patients who died of IE had normal ESR prior to death. At the time of the operation or death, ESR values were not different in the patients with or without cardiac abscesses detected at surgery or at autopsy.
White blood cell count
WBC on admission and peak WBC
WBC counts were available in 133 episodes. WBC was within reference values on admission in 47 episodes and remained so throughout the illness in 21 episodes. WBC was highest in IE caused by pneumococci and lowest in IE caused by coagulase-negative staphylococci (Table 2).
Changes of WBC count during treatment
WBC counts were significantly (RANOVA) higher throughout the illness in episodes with a complicated course of IE than in those with an uncomplicated course of IE (P<0.001) and also significantly higher in episodes with a fatal outcome than in those with a favourable outcome (P<0.001). No difference was observed between the episodes ending in cardiac surgery and those that did not. The trend analysis showed that an increment of 5x109/L (SD of WBC, 4.2x109/L) in the WBC counts on week 2 after admission was associated with a 2.3-fold odds for death (OR=2.3, 95% CI, 1.24.5; P=0.01). In a similar analysis of the WBC counts on week 4, the OR for death was 3.1 (95% CI, 1.37.1; P=0.008).
Normalization of WBC count during treatment
The WBC count normalized in 110 episodes. The proportion of WBC counts that remained elevated during the treatment was significantly higher in patients with a complicated course of IE than in those with an uncomplicated course (Figure 1C). Similar differences were observed regarding episodes ending or not ending in surgery (Figure 2C) and episodes with a fatal or a favourable outcome (Figure 3C). Association between normal and elevated WBC counts over time and the outcome of IE is presented in Table 4. Elevated WBC counts were significantly associated with death, but despite the normal WBC counts, patients could develop complications.
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Cut-off points
By ROC analysis for the three laboratory tests on week 4, the highest overall accuracy (area under ROC curve, c-index) in prediction of death was found for C-reactive protein (c=0.770), the second highest for WBC (c=0.715), and the lowest for ESR (c=0.594). We searched for cut-off points of C-reactive protein, WBC, and ESR on week 4 that could predict death of a patient during the remaining follow-up with a sensitivity of at least 85% combined with the best possible specificity. For C-reactive protein, the concentration of 62 mg/L was identified as such a cut-off point. On week 4, the C-reactive protein value was 62 mg/L in 12 out of the 14 patients (sensitivity 85.7%) who died during the remaining follow-up, whereas the C-reactive protein value was <62 mg/L in 58 of the 80 patients (specificity 72.5%) who survived. The OR for death was 15.8 for the patients with the C-reactive protein values
62 mg/L when compared with those with the C-reactive protein values <62 mg/L (95% CI, 3.376.4; P<0.001). By the same criteria, the cut-off point for the WBC count on week 4 was 7.1x109/L; during the remaining follow-up, the sensitivity for death was 86.7% and the specificity 52.4%. The OR for death was 7.2 for the patients with WBC counts
7.1x109/L when compared with those with WBC counts <7.1x109/L (95% CI, 1.533.7; P=0.013). An ESR value of
36 mm/h had a sensitivity of 87.5% for death, but the specificity was 30.7%. The OR showed no excess mortality for high ESR values.
When the association of death with the cut-off points of C-reactive protein and WBC were analysed at the same time, it was found that C-reactive protein significantly (P=0.005) predicted the death. After adjusting for the use of C-reactive protein, the cut-off point for the WBC count had no additional independent prognostic value for death.
The ROC curves demonstrated that corresponding to practically any fixed level of the sensitivity, the specificity of C-reactive protein in predicting death during the follow-up stayed higher than the specificity of WBC or ESR (Figure 4). Inversely, for a fixed specificity, the sensitivity was higher for C-reactive protein than for WBC or ESR.
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Discussion |
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These results statistically validate observations made in earlier studies that a progressive decline of C-reactive protein towards normal reflects a favourable response to antimicrobial therapy, whereas a sustained elevation of C-reactive protein implies a potential failure of therapy,68 inciting a clinician to look for complications.
The present study differs from earlier studies on IE in that extensive and modern statistical analyses were performed to seek more information of the utility of C-reactive protein, WBC, and ESR as markers of the therapeutic response. Special efforts were made to define markers predicting either a poor or a favourable outcome of IE, which could be plausibly useful in clinical practice. In our patients, the C-reactive protein level 62 mg/L on week 4 proved to be a cut-off point predicting death during the follow-up with a diagnostic sensitivity of 85.7% and a specificity of 72.5%. Also a WBC count
7.1x109/L on week 4 predicted death with a sensitivity of 86.7%, but the specificity was only 52.4%. Furthermore, the fact that this WBC cut-off point lies in the middle of the WBC reference values makes it completely useless as a clinical marker.
One of the main findings of the present work was that during the follow-up, high C-reactive protein values were significantly associated with a complicated course of IE and fatal outcome. Yet, mere knowledge of the positive association between high C-reactive protein values and eventual death does not offer much practical help to a clinician who is attending an individual patient. This was clearly demonstrated in our patients, in whom prolonged elevation of C-reactive protein values did not regularly predict a poor prognosis, as even 56 of the 81 patients (69%), who had elevated C-reactive protein still on week 6, recovered without complications. In direct contrast, the finding that the C-reactive protein value normalizes during treatment proved very useful, as normal C-reactive proteins were associated with an invariably good prognosis in our patients. Indeed, none of the 80 patients who had normal C-reactive protein by week 10 died of IE. Moreover, none of the 22 patients whose C-reactive protein normalized by week 4 needed cardiac surgery and only two of the 33 patients whose C-reactive protein normalized by week 6 needed cardiac surgery, both in spite of the fact that the medical treatment of IE was successful (Table 3). On the basis of these findings, we believe that normalization of the C-reactive protein value may be clinically the most useful laboratory finding during the treatment of IE, because it demonstrates that the patient has responded to therapy and reliably predicts a favourable outcome.
Also the fall in the WBC count was significantly faster when a patient had an uncomplicated recovery of IE than when complications developed or death ensued. However, although elevated WBC counts were associated with death, normal WBC counts did not invariably predict a good prognosis (Table 4). Thus, normalization of WBC count was less useful than normalization of C-reactive protein value as a tool to monitor the outcome of IE.
Perhaps, the most demanding task for a clinician attending a patient with IE is to decide when and whether to recommend valve surgery. Therefore, it would be extremely meaningful to find some limits for laboratory markers of inflammation, which could give support to a decision either to pursue or to delay the operation. We showed here that the C-reactive protein values were constantly higher in the patients who required valve surgery when compared with those who recovered with conservative treatment. Moreover, all patients who needed surgery within 4 weeks from admission had elevated C-reactive protein values at the time of surgery (Figure 2A). Unfortunately, the present study design did not allow us to define any limits for the C-reactive protein value, which would predict a fatal outcome in case the operation is delayed. Neither do we believe that any reasonable limits for C-reactive protein could be defined that, in and of itself, would necessitate surgery, since a decision to operate cannot be based on the levels of infection parameters only.
Although single values of acute phase parameters are seldom useful to guide therapeutic decisions, they may provide additional help, for example, when a clinician is choosing empiric antimicrobial treatment and has to decide between a tentative diagnosis of acute and a subacute endocarditis. In accordance with other investigators,6,9 we noted that high C-reactive protein values and WBC counts on admission correlate with the severity of the disease and with the virulence of the causative agents. High C-reactive protein values and WBC counts were typical findings in patients with a short duration of symptoms and with either S. aureus or S. pneumoniae as causative agents. These features are characteristic of acute IE. In contrast, a long duration of symptoms and the presence of viridans streptococci or enterococci as causative agents, which are characteristic features of subacute IE, were associated with low C-reactive protein values and with low WBC counts. On admission, C-reactive protein and ESR were significantly lower in the patients with prosthetic valve IE than in those with native valve IE. This may be due to less virulent causative microorganisms of prosthetic valve IE as well as a lower occurrence of clinical events, especially peripheral emboli, in our patients with prosthetic valve disease.
In agreement with previous studies,9,10 the serum C-reactive protein value was here the most sensitive laboratory test to detect infection. On admission, C-reactive protein was elevated in all episodes of IE, whereas ESR was normal in 14 episodes and WBC count was normal in 47 episodes. Moreover, ESR values and WBC counts remained normal during the entire illness in five and 21 episodes of IE, respectively. C-reactive protein was also sensitive to detect a poor recovery. All patients who died of IE had elevated C-reactive protein values before death, whereas five (18.5%) and 11 (40.7%) patients had normal ESR values and normal WBC counts, respectively, at the time of death. The higher sensitivity and specificity of C-reactive protein in predicting death when compared with WBC or ESR was demonstrated here also by the ROC curves (Figure 4). On the whole, the changes of ESR during the treatment and the development of IE-related complications were not associated. Thus, ESR is not a useful marker for monitoring a patient's response to therapy in IE.
The reason why C-reactive protein has not been adopted in universal use may be the fact that according to the conclusions of some studies and critical reviews, the C-reactive protein value alone cannot be used to differentiate between bacterial and viral infection, or for instituting or withholding antimicrobial therapy on a patient's admission to hospital.17,18 According to these same reviews, however, once a firm diagnosis of an infectious disease has been made, serial measurements of C-reactive protein are useful in monitoring of the patient's response to therapy.17,18 The results of the present study indicate that this principle is valid also in patients with IE.
The period of this study was as long as 20 years. One must, therefore, bear in mind that during these long years, there may have been some changes in the management and mortality of IE. In the patients studied here, however, no changes in mortality were observed.
In conclusion, the normalization of C-reactive protein proved to be a good predictor of a favourable late outcome (surgery, death) of IE. Also WBC count proved useful in the clinical assessment of patients with IE, but the value of ESR was negligible.
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Acknowledgements |
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References |
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