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Procalcitonin is not a reliable marker for the assessment of severity in acute pancreatitis without infectious complications.

The clinical spectrum of acute pancreatitis (AP) ranges from mild, self-limiting symptoms to a fulminating, rapidly lethal disease. Early objective identification of the risk of major complications or death is essential for appropriate management of individual patients and for the efficacy of treatment. However, clinical judgment alone is of low sensitivity in predicting severity and outcome in AP (1), and clinicobiochemical criteria such as those of Ranson (2) and Blamey et al. (3) suffer from a lack of simplicity and a 48-h delay in final assessment. Radiological methods enable a reliable diagnosis of necrotizing pancreatitis, but their availability often is limited (4). Several newer single-factor markers have been described as being effective in identifying severe AP. The acute phase reactant, C-reactive protein (CRP), is a most useful single marker that is cheap and easy to measure, but it also requires 48 h for maximal response (5, 6).

Recently, procalcitonin (PCT), a 116-amino acid propeptide ([M.sub.r] 13 000) of calcitonin with a long half-life in the systemic circulation, was found in high concentrations in patients with severe bacterial or fungal infections and sepsis (7), and it was reported as a marker in assessing the infection of necrotizing pancreatitis in late-stage disease (8) and in evaluating the biliary origin of the AP (9). In contrast to the classical acute-phase protein CRP, PCT is not increased after operative trauma (10). The aim of this study was to examine the ability of PCT to provide early prediction of severity and to assess the etiology of AP and in addition examine the relationship between PCT and the acute phase protein, CRP.

We studied 31 consecutive patients with AP (14 males and 17 females; mean age, 66.4 years; range, 34-87 years), with onset of pain <24 h before admission. We measured serum PCT and CRP within the first 24 h after admission. The diagnosis of AP was based on typical clinical symptoms associated with at least a twofold increase in serum lipase, and was confirmed by abdominal ultrasonography and/or contrast-enhanced computed tomography. In 25 patients, pancreatitis was of biliary origin (defined by one or more of the following criteria: increased cholestasis laboratory parameters, history of gallstones, and presence of dilated common bile duct and biliary sludge and/or stones by ultrasonography and/or contrast enhanced computed tomography and/or endoscopic retrograde cholangiography). In the six other patients, the pancreatitis was attributable to alcohol abuse in one and of unknown origin in five.

[FIGURE 1 OMITTED]

The severity of pancreatitis was assessed on the basis of the Atlanta criteria (11), which are largely used to assess a posteriori the severity of AP. In brief, these criteria define AP as mild if local and/or systemic complications are absent or are present with only minimal organ dysfunction; the pancreatitis is defined as severe if local complications (necrosis, pseudocysts, or abscess) and/or one or more organ dysfunctions are present. According to the Atlanta criteria, the pancreatitis was mild in 19 patients and severe in 12.

The 31 healthy subjects included in the present study were in general good health, free from medication, and without clinical or laboratory signs of hepatic, biliary, renal, intestinal, or endocrinological malfunction.

After study participants gave informed consent, blood samples were taken on admission and then daily for 5 days. All serum samples were stored at -20[degrees]C until assayed. All samples were analyzed in duplicate within 6 months of collection. PCT was measured by a manual procedure with an immunoluminometric assay (12) (LUMI test PCT; Brahms Diagnostica GmbH) that requires ~180 min to perform. Serum CRP was determined using a nephelometric technique (CRP; Dade Behring). The inter- and intraassay analytical imprecision (CV) for the two markers was as follows: 11% and 19% for PCT (mean, 0.62 [micro]g/L), and 2.7% and 4.9% for CRP (mean, 4.8 mg/L), respectively. The upper reference limits reported in the package inserts for PCT and CRP were 0.5 [micro]g/L and 5.0 mg/L, respectively. All statistical evaluations were performed with the SPSS/PC1 statistical package on a personal computer. The data were not gaussian distributed; therefore, a nonparametric test was used.

During the first 6 days, the concentrations of CRP and PCT in the patients with pancreatitis were significantly higher than those in healthy subjects (P <0.001, Mann-Whitney U-test). As shown in Fig. 1, the peak for both CRP and PCT in the severe group was observed at the 3-day time point. PCT in the mild group was not significantly different from that in the severe group at any point in the study, whereas the CRP was significantly lower in the mild group than in the severe group on days 2-6. The values of all samples obtained from the 31 patients were pooled and used for the calculation of the best cutoff for the two markers. Receiver-operating curves in differentiating between severe and mild disease showed that CRP had a larger area under the curve than did PCT (0.776 [+ or -] 0.026 vs 0.456 [+ or -] 0.036; P <0.001) (13, 14). The cutoff value, with maximal likelihood ratios (15), was 0.252-0.255 [micro]g/L for serum PCT and 128-129 mg/L for serum CRP. (These cutoff values represent the range in which the likelihood ratio did not change.) The sensitivity and specificity of the two markers at these cutoffs in assessing the severe form of AP for the entire period are reported in Table 1. No significant differences in PCT or CRP were found between patients with biliary and nonbiliary AP.

Our data confirm that CRP is a good marker of severity in later stages of AP. PCT has been proposed as a marker for the noninvasive, accurate prediction of infected necrosis as well as for the selection of patients with persisting septic complications after surgical debridement (8). In our population, PCT serum concentrations were similar in patients with severe AP and in those with the mild form of the disease. The absence of a significant difference is in accordance with the clinical course of patients who did not develop infectious complications. In fact, only 1 of our 12 patients with severe pancreatitis underwent pancreatic surgery because of infected necrosis; he died on the fifth day. Even this patient's serum PCT was lower than the upper reference limit.

In conclusion, our data indicate that CRP is better than serum PCT in assessing in severity of AP. However, we cannot exclude that PCT could be useful in detecting and following patients with AP with infectious complications because PCT appears to be one of the best indicators of bacterial sepsis (7, 10) and a useful marker of the severity of infection (16), although much remains to be understood about its role in normal physiology and in sepsis (17). The possible role of PCT as a marker for biliary pancreatitis is still controversial. Rau et al. (8) found no correlation between the etiology of AP and PCT, whereas Brunkhorst et al. (9) reported that PCT may be an early marker of biliary pancreatitis. Our data, although based on a limited number of patients, are in agreement with the findings of Rau et al. (8), indicating that PCT is an insensitive marker for the recognition of the biliary etiology of AP.

This study was supported by University Hospital Policlinico S. Matteo of Pavia, Italy.

References

(1.) Cornfield AP, Cooper MJ, Williamson RCN, Mayer AD, MacMahon MJ, Dickson AP, et al. Prediction of severity in acute pancreatitis: prospective comparison of three prognostic indices. Lancet 1985;ii:403-7.

(2.) Ranson IHC. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982;77:633-8.

(3.) Blamey SL, Imrie CW, O'Neil J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984;25:1340-6.

(4.) Neoptolemos JP, Carr-Locke DL, London NJ, Bailey IA, James D, Fossard DP. Controlled trial of urgent endoscopic retrograde cholangiopancreatography versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988;ii:979-83.

(5.) Puolakkainen P, Valtonen V, Paananen A, Schroder T. C-reactive protein (CRP) and serum phospholipase A2 in the assessment of the severity of acute pancreatitis. Gut 1987;28:764-71.

(6.) Wilson C, Heads A, Shenkin A, Imrie CW. C-reactive protein, antiproteases and complement factors as objective markers and severity in acute pancreatitis. Br J Surg 1989;76:177-81.

(7.) Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515-8.

(8.) Rau B, Steinbach G, Gansauge F, Mayer JM, Grunert A, Beger HG. The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis. Gut 1997;41:832-40.

(9.) Brunkhorst FM, Eberhard OK, Brunkhorst R. Early identification of biliary pancreatitis with procalcitonin. Am J Gastroenterol 1998;93:1191-2.

(10.) Monneret G, Doche C. Vital Durand D, Lepape A, Bienvenu J. Procalcitonin as a specific marker of bacterial infection in adults. Clin Chem Lab Med 1998;38:67-8.

(11.) Bradley EL. A clinically based classification system for acute pancreatitis. Arch Surg 1995;128:586-90.

(12.) Bertsch T, Richter A, Hofheinz H, Bohm C, Hartel M, Aufenanger J. Procalcitonin. A new marker for acute phase reaction in acute pancreatitis. Langenbecks Arch Chir 1997;382:367-72.

(13.) Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29-36.

(14.) Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839-43.

(15.) Pezzilli R, Billi P, Miniero R, Fiocchi M, Cappelletti O, Morselli Labate AM, et al. Serum interleukin-6, interleukin-8, and [beta]-2-microglobulin in early assessment of severity of acute pancreatitis. Comparison with serum C-reactive protein. Dig Dis Sci 1995;40:2341-8.

(16.) Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 1999;27: 498-504.

(17.) Braithwaite SS. Procalcitonin--marker, or mediator? Crit Care Med 1998; 26:977-8.

(18.) Siegel S. Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill, 1956:30-4.

GianVico Melzi d'Eril, [1] * Giampaolo Merlini, [2] Sergio Finazzi, [1] Tiziana Bosoni, [3] Bahjart Barakat, [4] and Raffaele Pezzilli [4] ([1] Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Universita degli Studi dell'Insubria, Ospedale di Circolo, 21100 Varese, Italy; [2] Laboratorio Ricerca Biotecnologie, IRCCS Policlinico S. Matteo, Dipartimento di Biochimica, Universita degli Studi di Pavia, 27100 Pavia, Italy; [3] Laboratorio di Analisi Chimico Cliniche, IRCCS S. Matteo, 27100 Pavia, Italy; [4] Servizio di Medicina di Urgenza e Pronto Soccorso, Ospedale S. Orsola, 40138 Bologna, Italy; * author for correspondence: fax 39-0332-265586, e-mail gvmdeuni@ unipv.it)
Table 1. Sensitivity and specificity of PCT and CRP in assessing the
severity of AP. (a)

 Day 1 Day 2 Day 3

Sensitivity,
 PCT 8.3 16.7 25.0
 CRP 8.3 66.7 83.3
 PCT vs CRP P = 1.00 P = 0.031 P = 0.016
Specificity,
 PCT 78.9 78.9 89.5
 CRP 100.0 89.5 84.2
 PCT vs CRP P = 0.125 P = 0.625 P = 1.000

 Day 4 Day 5 Day 6

Sensitivity,
 PCT 33.3 27.3 20.0
 CRP 75.0 63.6 70.0
 PCT vs CRP P = 0.125 P = 0.289 P = 0.125
Specificity,
 PCT 88.2 80.0 83.3
 CRP 82.4 86.7 91.7
 PCT vs CRP P = 1.000 P = 1.000 P = 1.000

(a) Sensitivities and specificities of PCT and CRP were compared by
means of the McNemar test (18).
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Title Annotation:Technical Briefs
Author:d'Eril, GianVico Melzi; Merlini, Giampaolo; Finazzi, Sergio; Bosoni, Tiziana; Barakat, Bahjart; Pezz
Publication:Clinical Chemistry
Date:Mar 1, 2000
Words:1942
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