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Eur J Cardiothorac Surg 2005;27:1074-1078
© 2005 Elsevier Science NL


Usefulness of procalcitonin in the early detection of infection after thoracic surgery

Pierre-Emmanuel Falcoza,*, Fréderic Laluca, Marie-Madeleine Toubinb, Marc Puyraveauc, François Clementa, Mariette Mercierc, Sidney Chocrona, Joseph-Philippe Etieventa

a Department of Thoracic and Cardiovascular Surgery, Jean-Minjoz Hospital, Boulevard Fleming, 25000, Besançon, France
b Department of Medical Biochemistry, Saint-Jacques Hospital, Besançon, France
c Department of Biostatistics and Epidemiology, Medical School, Besançon, France

Received 21 November 2004; received in revised form 20 February 2005; accepted 21 February 2005.

* Corresponding author. Tel.: +33 3 81668664; fax: +33 3 81668661. (E-mail: pierre-emmanuel.falcoz{at}wanadoo.fr).


    Abstract
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: The twofold aim of this prospective clinical study was to assess the accuracy of procalcitonin as a marker of postoperative infection after thoracic surgery and to compare it with C-reactive protein. Methods: Procalcitonin and C-reactive protein concentrations, clinical symptoms of infection and systemic inflammation were recorded preoperatively and 5 days postoperatively in 157 patients undergoing the following procedures: 52 wedge resections, 28 pneumonectomies and 77 lobectomies (or bilobectomies). Patients were classified as non-infected or infected according to predefined criteria. Results: In non-infected patients (n=132), procalcitonin peaked on day 1 and C-reactive protein, on day 2. The procalcitonin value was significantly higher in patients having undergone a pneumonectomy (0.73±0.78 versus 0.54±0.25ng/mL for lobectomy and 0.50±0.35ng/mL for wedge resection; P=0.04). The mean value of procalcitonin was significantly higher in patients with postoperative infection (n=25) than in those with no postoperative infection (3.6±5.5 versus 0.63±0.62ng/mL; P=0.0001). The onset of infection most frequently occurred on postoperative day 2 (43% of patients); maximum procalcitonin and C-reactive protein concentrations most frequently appeared on postoperative day 1 (56% of patients) and day 2 (63% of patients), respectively. The best cutoff value for detection of infection with procalcitonin was 1ng/mL and with C-reactive protein, 100mg/L. Comparing the area under the Receiver Operating Characteristic curves, procalcitonin was better than C-reactive protein for detecting postoperative infection (0.92 versus 0.66; P<0.0001). Conclusions: Procalcitonin can be used as a reliable diagnostic parameter to detect and to monitor infectious complications in the postoperative period after thoracic surgery, especially in patients felt to be at higher risk (SIRS). It provides more information about the course of the disease than C-reactive protein does, and can be detected before the occurrence of clinical infection.

Key Words: Biochemistry • Complications of surgery • General thoracic surgery • Lung infection • Morbidity • Procalcitonin


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Procalcitonin (PCT) is a precursor of calcitonin in humans [1]. Usually undetectable in healthy subjects, it has been proposed as an early, sensitive, and specific indicator of sepsis [2–5]. To date, very little is known about the value of PCT after adult thoracic surgery. To the best of our knowledge, only two studies—one by Meisner published in 1998 [6] and the other by Molter in 2003 [7]—have included subgroups of thoracic surgical patients in groups of patients undergoing different types of surgery. Thus, it appeared worthwhile to design a specific study dealing with thoracic surgery.

The aim of this prospective clinical study was twofold: to assess the accuracy of PCT as a marker of postoperative infection after thoracic surgery and to compare it with C-reactive protein (CRP).


    2. Materials and methods
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
2.1. Patient population
From June 2003 through June 2004, a total of 188 patients underwent thoracic surgery in the Department of Thoracic and Cardiovascular Surgery at the University Hospital in Besançon (France). Not included in this study were patients: having a proven preoperative infection (9 out of 188, 4.8%), requiring unscheduled surgery (14 out of 188, 7.4%), or unable to give written informed consent (3 out of 188, 1.6%). Five additional patients (2.7%) refused to participate. In all, 157 (83.5%) patients gave their written informed consent and were enrolled in the study, performed according to the principles of the Declaration of Helsinki.

2.2. Procedure
The following data were registered preoperatively (shortly before induction of anesthesia), at hours 8 and 12 following surgery, and daily until postoperative day 5: body temperature, cardiac rhythm, clinical signs of infection or inflammation, white blood cell counts, serum levels of CRP and PCT. Chest radiography was performed preoperatively and daily until postoperative day 5. In addition, based on the registered data, the American College of Chest Physicians definition criteria for systemic inflammatory response syndrome (SIRS) and sepsis were evaluated in all patients [8]. A 24-h perioperative antibiotic prophylaxis was administered to all patients using cefuroxime (Zinnat®, GlaxoSmithKline, Marly-le-Roy, France): 1.5g at the induction of anesthesia, 750mg every 2h during surgery, and 750mg every 8h for 24h following surgery. Chest physiotherapy was started immediately on arrival in the intensive care unit, and early mobilization, usually on postoperative day 1, was implemented.

Diagnosis of postoperative infection was done by bedside clinical examination, systematic screening included chest radiography, leukocyte counts, blood cultures (BACTECPLUS, Becton Dickinson Diagnostic Instrument Systems, Sparks, MD) and, if pneumonia or atelectasis was suspected, bronchial secretion cultures obtained by endotracheal suction. Bacteriological samples were drawn in patients before any antibiotic treatment, other than the systematic perioperative antibiotic prophylaxis. Data collected regarding postoperative infections were blinded to PCT level results. Assessment of infection was defined as the postoperative occurrence of either: pneumonia, empyema, bronchopleural fistula, or wound infection. Postoperative pneumonia was suspected if purulent sputum (yellow or green) was collected or bronchial secretion showed more than 25 leukocytes and yielded growth of relevant pathogens on culture and if at least two of the following criteria were met: (1) white blood cell count greater than 12,000/mm3, (2) body temperature above 38°C, and (3) new or increasing lung infiltrate or atelectasis on conventional chest radiograph. Definitive diagnosis of pneumonia was established in accordance with the definitions of the Centers for Disease Control and Prevention [9]. Each patient presenting the aforementioned criteria of postoperative infection received systematic antibiotic treatment with amoxicillin and clavulanate (Augmentin®, GlaxoSmithKline, Marly-le-Roy, France): 3x1g per day until antibiogram results were received, at which point the treatment was adapted to pathogen(s) involved. Patients were then classified according to their postoperative infectious status into two groups: non-infected patients and infected patients. Mortality was defined as in-hospital death at any time during the postoperative hospitalization period or death within 30 days of surgery.

2.3. Blood sampling and laboratory method
All members of our interdisciplinary team were blinded to the PCT values. All PCT assays were processed at our central laboratory. PCT samples were centrifuged and immediately frozen and stored at –70°C. Assays were performed in batches at the end of the study period. Each of the assays lasted 11/2;h. The circulating PCT level was measured by LUMItest PCT (BRAHMS Diagnostica GmbH, Berlin, Germany). This immunolumimetric assay is based on the reaction of two antigen-specific monoclonal antibodies that bind procalcitonin (as an antigen) to calcitonin and katacalcin segments. The inter-assay precision of the kit is 6–10%, the lower limit of detection was 0.08ng/mL, and the normal range for hospital inpatients was found to be <0.5ng/mL. A particle-enhanced turbidimetric immunoassay technique was used to determine the CRP level (IMMAGE, Beckman Coulter Inc., Fullerton, CA). A normal CRP value is less than 5mg/L. The white blood cell count was performed using the ADVIA 60 counter (Bayer Vital GmbH, Leverkusen, Germany). A normal white blood cell count is less than 12,000/mm3.

2.4. Statistical analysis
We analyzed the comparability of the infected and the non-infected group by the {chi}2 test (or Fisher's exact test), the two-group t-test, or the Mann–Whitney-U test, as appropriate. Analysis of variance/covariance, adjusted on pack-year history in smokers and duration of the operation, was used to compare PCT and CRP concentrations in the two groups.

Sensitivity, specificity, and predictive values of PCT and CRP for discrimination between infected and non-infected patients were calculated. The best cutoff value for both serum PCT and CRP was chosen as the value that optimized sensitivity, specificity, and predictive values. Receiver operating characteristic (ROC) curves were plotted, and the respective areas under them were calculated. The areas under the ROC curves were compared using the Z statistic (two-tailed test).

Data analysis was anonymous and data collection and processing were approved by the institutional review board of our hospital. All statistical analyses were performed with SAS software, version 8.02 (SAS Institute Inc., Cary, NC). Discrete variables are expressed as counts (%) and continuous variables as mean±standard deviation, unless otherwise stated. A P-value ≤0.05 was considered statistically significant.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
3.1. Characteristics of the study population (n=157)
Perioperative characteristics of patients included in this study are summarized in Table 1. Of the 157 patients evaluated, 132 had a course without infection, whereas 25 presented a postoperative infection. Among the baseline patient characteristics, pack-year history in smokers, duration of surgery and duration of stay in intensive care unit were associated with the diagnosis of postoperative infection. Among the 105 patients with lung cancer, 83 (79%) had primary lung cancer and 22 (21%) pulmonary metastases from other malignancies. Of the 52 wedge resections procedures, 39 (75%) were performed by video-assisted thoracic surgery. Overall, bacterial cultures were grown from sputum, bronchial secretion or both in 54 patients (34%), and from blood in 8 (0.05%). All 25 infected patients presented the same final diagnosis of postoperative pneumonia (microbiologically documented in 44% of cases); none had bronchopleural fistula, empyema or wound infection. Two of the 25 infected patients had mechanical ventilation at the time diagnosis of pneumonia.


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Table 1. Baseline patient characteristics
 
In the present study, from the standpoint of non-infective postoperative complications, there were no differences between groups, except for atrial fibrillation (5 out of 25 patients in the infected group versus 7 out of 132 in the non-infected group; P=0.025). Two patients (1.3%), one in each group, died. The first patient was a 69-year-old man with a past medical history of coronary disease. He had an uneventful postoperative course in terms of infection until day 4, when he had a massive pulmonary embolism causing death. The second patient, a 60-year-old man in a state of cachexia, was operated on for primary lung cancer. We performed a right inferior lobectomy extended to the chest wall. He died of extensive bacterial pneumonia and septic shock on day 5.

3.2. Markers in non-infected patients (n=132)
Fig. 1 shows the PCT and CRP kinetics during the perioperative period for the 132 patients with no postoperative infection. Baseline PCT concentration was 0.23±0.17ng/mL. PCT concentration increased significantly compared to the baseline concentration, with a peak on day 1: 0.37±0.58ng/mL (P=0.02). PCT levels then decreased rapidly and values returned to preoperative levels by day 3. Baseline CRP concentration was 9.15±18.66mg/L. CRP concentration increased significantly versus baseline with a peak on day 2: 69.68±47.13mg/L (P=0.0001). The PCT value was significantly higher in patients having undergone a pneumonectomy (0.73±0.78ng/mL versus 0.54±0.25ng/mL for lobectomy and 0.50±0.35ng/mL for video-surgery; P=0.04). The median CRP value was high in all patients irrespective of the group. PCT concentrations rose moderately above the normal range (≤0.5ng/mL) in 35% of patients and exceeded 1ng/mL in 3.8%, whereas CRP increased in all patients.



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Fig. 1. Postoperative serum procalcitonin and C-reactive protein kinetics in patients with no postoperative infection. PCT concentrations at day 1, day 2 and day 3 were significantly different (P<0.05) from the baseline PCT concentration, whereas CRP concentrations were systematically and significantly different (P<0.001) from the baseline CRP concentration. Values are expressed as mean±standard error of the mean. CRP, C-reactive protein; D, day; H, hour; PCT, procalcitonin.

 
3.3. Markers in infected patients (n=25)
The mean value of PCT was significantly higher in patients with postoperative infection than in those with no postoperative infection (3.6±5.5 versus 0.63±0.62ng/mL; P=0.0001; Fig. 2). The median value of PCT in infected patients was 1.94ng/mL with a maximum of 25.9ng/mL. PCT and CRP concentrations had increased in 96% (all but one) and 100% of patients, respectively. In terms of level of PCT, no difference was found between patients with radiological criteria of atelectasis and others (P>0.2). Infection most frequently occurred on day 2 (43% of patients), whereas maximum PCT and CRP concentrations occurred on postoperative day 1 (56% of patients) and day 2 (63% of patients), respectively.



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Fig. 2. Procalcitonin concentrations in patients with and without postoperative infection. Data are depicted as box plot diagrams (logarithmic scale). The box represents the range of values from the 10% percentile (lower bar) to the 90% percentile (upper bar). The horizontal line within the box represents the median and the vertical line signifies the maximum and minimum values. The horizontal line between the boxes represents the best cutoff as an indicator of infection (1ng/mL).

 
The area under the ROC curve that used PCT to detect postoperative infection was 0.92 (95% CI, 0.87–0.96). In comparison, the area under the ROC curve that used CRP to detect postoperative infection was considerably lower: 0.66 (95% CI, 0.58–0.73); P<0.0001 (Fig. 3). The optimum concentration of PCT for the calculation of positive and negative predictive accuracy as obtained from the ROC curve was 1ng/mL. With this cutoff, the test characteristics of PCT were as follows: 88% sensitivity, 90% specificity, 63% positive predictive value and 97.5% negative predictive value. For detection of infection by CRP, a value of 100mg/L showed 43% sensitivity, 84% specificity, a 36% positive predictive value and an 88% negative predictive value.



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Fig. 3. Receiver Operating Characteristic curves for the ability of procalcitonin and C-reactive protein to detect postoperative infection. Area under the ROC curve for PCT was 0.92 (95% CI, 0.87–0.96) compared with 0.66 (95% CI, 0.58–0.73) for CRP; P<0.0001. CRP, C-reactive protein; PCT, procalcitonin; ROC, receiver operating characteristic.

 

    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
This study assessed the accuracy of PCT in diagnosing infection following thoracic surgery in a consecutive patient cohort. We found PCT to be significantly higher in patients with a postoperative infection than in patients with no postoperative infection. The area under the ROC curve that used PCT to detect postoperative infection was 0.92 (95% CI, 0.87–0.96), compared to 0.66 (95% CI, 0.58–0.73) for CRP. These findings suggest that PCT is a valuable additional diagnostic marker of postoperative infection after thoracic surgery. It also indicates the poor diagnostic value of CRP. In addition, when focusing on non-infective postoperative complications (e.g. atrial fibrillation, myocardial infarction, renal insufficiency...), there are no differences in PCT values between patients with and without postoperative infection (data not shown).

In the present study, a PCT value of 1ng/mL was found to be the best cutoff value for diagnosis of infection. Thus, in patients with no postoperative infection, a PCT level which is <1ng/mL or steadily decreases is reassuring and may be helpful in deciding on a safe early discharge. Effectively, the negative predictive value of a PCT level below 1ng/mL in the diagnosis of postoperative infection was 97.5%. However, using the threshold of 1ng/mL for diagnosis of infection, five patients were falsely positive in our study (PCT was >1ng/mL in the absence of infection). For these five patients, the increase in PCT concentration in the absence of infection was the result of a persistent postoperative SIRS. Increase in PCT values has been reported previously in patients with SIRS and lung injury. Both Meisner [6] and Molter [7] reported a postoperative increase in PCT values in patients suffering from SIRS in the absence of infection. It is especially noteworthy that the median PCT value we obtained with these five patients was much closer to the median PCT value in Meisner's study [6]: 1.32 and 1.61ng/mL, respectively. Hensel [10] also showed high PCT values in patients with acute lung injury after cardiac surgery in the absence of infection. On the other hand, with the 1ng/mL cutoff, one of our patients with criteria for pneumonia was falsely negative (PCT was <1ng/mL in the presence of proven infection). Apart from the fact that this patient had had preoperative chemotherapy, no satisfactory explanation was found for this discordance in findings.

A result that might be somewhat disturbing to readers is that the 63% positive predictive value we calculated with a PCT cutoff of 1ng/mL is relatively low. However, the positive predictive value depends on the prevalence of the disease in a given population [11]. In the present study, the prevalence of infection was 16%. If we had performed a post hoc analysis by restricting the scope of this work to the 40 patients with SIRS criteria (body temperature >38°C and a ventricular rate >90 beat per minute), the prevalence would have been 62.5% and the positive predictive value, therefore, 90%. Comparing the patients presenting with or without postoperative SIRS, a significant difference in PCT concentration between groups was observed (1.89±4.65ng/mL in patients with SIRS versus 0.82±0.83ng/mL in patients without SIRS; P=0.01). Accordingly, combining SIRS criteria with PCT levels allows to detect patients at risk for infection and help to select those in whom antibiotic prophylaxis should be transformed into early curative treatment.

Interestingly, another study on the diagnostic role of PCT in early detection of infection after cardiac surgery [12] used the same cutoff value as ours—1ng/mL. PCT has also been found useful in differentiating bacterial infection from acute rejection after heart and lung transplantation [13]. In this circumstance, a PCT value >1ng/mL was considered suggested of infection. Similar results have been reported in liver [14] and renal transplanted patients [15].

One limitation does need to be mentioned. Although this study was built to take into account all types of postoperative infection, the population of patients studied only developed pneumonia. Obviously, our observations need to be confirmed in further studies before definite recommendations can be made regarding the use of PCT during the postoperative course of thoracic surgery in general and the optimal cutoff value of PCT in particular.

In conclusion, PCT can be used as a reliable diagnostic marker to detect and to monitor infectious complications in the postoperative period after thoracic surgery, especially in patients felt to be at higher risk (SIRS). It provides more information about the course of the disease than CRP does, and can be detected before the occurrence of clinical infection.


    Acknowledgments
 
The authors thank Nancy Richardson-Peuteuil for her editorial assistance. To my daughter Pauline who left this world too soon.


    Footnotes
 
{star} Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


    References
 Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Ghillani PP, Motte P, Troalen F, Julienne A, Gardet P, Le Chevallier T, Rougier P, Schlumberger M, Bohuon C, Bellet D. Identification and measurement of calcitonin precursors in serum patients with malignant diseases. Cancer Res 1989;49:6845-6851.[Abstract/Free Full Text]
  2. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infections. Lancet 1993;341:515-518.[CrossRef][Medline]
  3. Al-Nawas B, Krammer I, Shah PM. Procalcitonin in diagnosis of severe infections. Eur J Med Res 1996;1:331-333.[Medline]
  4. Oczenski W, Fitzgerald RD, Schwarz S. Procalcitonin: a new parameter for the diagnosis of bacterial infection in the peri-operative period. Eur J Anaesth 1998;15:202-209.[CrossRef][Medline]
  5. Reith HB, Mittelkötter U, Debus ES, Lang J, Thiede A. Procalcitonin in early detection of postoperative complications. Dig Surg 1998;15:260-265.[CrossRef][Medline]
  6. Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intens Care Med 1998;24:680-684.[CrossRef][Medline]
  7. Molter GP, Soltész S, Kottke R, Wilhelm W, Biedler A, Silomon M. Procalcitonin plasma concentrations and systemic inflammatory response following different types of surgery. Anaesthesist 2003;52:210-217.[CrossRef][Medline]
  8. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74..
  9. Garner JS. CDC definitions for nosocomial infections. Am J Infect Control 1988;16:128-140.[CrossRef][Medline]
  10. Hensel M, Volk T, Docke WD, Kern F, Tschirna D, Egerer K, Konertz W, Kox WJ. Hyperprocalcitonemia in patients with noninfectious SIRS and pulmonary dysfunction associated with cardiopulmonary bypass. Anesthesiology 1998;89:93-104.[CrossRef][Medline]
  11. Mittendorf R, Pryde P, Herschel M, Williams M. Is routine antenatal toxoplasmosis screening justified in the United States? Statistical considerations in the application of medical screening tests. Clin Obstet Gynecol 1999;42:163-173.[Medline]
  12. Aouffi A, Piriou V, Bastien O, Blanc P, Bouvier H, Evans R, Celard M, Vandenesch F, Rousson R, Lehot JJ. Usefulness of procalcitonin for diagnosis of infection in cardiac surgical patients. Crit Care Med 2000;28:3171-3176.[CrossRef][Medline]
  13. Hammer S, Meisner F, Dirschedl P, Hobel G, Fraunberger P, Meiser B, Reichardt B, Hammer C. Procalcitonin: a new marker for diagnosis of acute rejection and bacterial infection after heart and lung transplantation. Transpl Immunol 1998;6:235-241.[Medline]
  14. Kunz D, Pross M, Konig W, Lippert H, Manger T. Diagnostic relevance of procalcitonin, IL-6 and cellular immune status in the early phase after liver transplantation. Transpl Proc 1998;30:2398-2399.[Medline]
  15. Eberhard OK, Langefeld I, Kuse ER, Brunkhorst FM, Kliem V, Schlitt HJ, Pichlmayr R, Koch KM, Brunkhorst R. Procalcitonin in the early phase after renal transplantation–will it add to diagnostic accuracy?. Clin Transpl 1998;12:206-211.



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