Pediatr Surg Int DOI 10.1007/s00383-014-3585-8
ORIGINAL ARTICLE
Hyperfibrinogenemia in appendicitis: a new predictor of perforation in children Shaoguang Feng • Peng Wu • Xiaoming Chen
Accepted: 5 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Acute appendicitis is the most common emergency abdominal inflammation requiring operation in children. As an acute-phase protein, plasma fibrinogen always increases with inflammation or tissue necrosis. This had brought about the assumption that hyperfibrinogenemia in patients with appendicitis may have a predictive ability for the preoperative diagnosis of appendiceal. Aim of this retrospective study was to assess the diagnostic value of hyperfibrinogenemia as a preoperative laboratory marker for appendiceal perforation in children with acute appendicitis. Methods We screened 466 children (168 girls, 298 boys, mean age, 7.6 years) with histologically confirmed acute appendicitis who received laparoscopic or open appendectomy between January 2012 and April 2014 in a pediatric surgery department of an academic teaching hospital. A retrospective review of the medical records including appendiceal perforation rate and laboratory results was conducted. Results Mean plasma fibrinogen level of all patients was 4.89 g/L (SD 1.74 g/L, range 1.94–15 g/L, median 4.61 mg/dL). Children with appendiceal perforation had a mean fibrinogen level of 6.18 g/L (SD 1.83 g/L, range 3.02–15 g/L, median 5.79 g/L), which was significantly higher than those with non-perforated children
S. Feng P. Wu Department of Pediatric Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China X. Chen (&) Department of Pediatric Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China e-mail: [email protected]; [email protected]
(P = 0.0001). The specificity of hyperfibrinogenemia for appendiceal perforation was 0.82 in comparison with 0.25 for white blood count (WBC) and 0.34 for C-reactive protein (CRP). Sensitivity was 0.74 compared with 0.76 for WBC and 0.94 for CRP. Conclusion Children with hyperfibrinogenemia and clinical symptoms of appendicitis may be regarded as a higher risk of appendiceal perforation than whose fibrinogen level is normal. Keywords Pediatric Perforated appendicitis Hyperfibrinogenemia Diagnosis
Introduction Acute appendicitis is one of the most common emergencies in children. Rate of appendiceal perforation occurs between 23 and 73 % in children [1]. Appendiceal perforation in children with acute appendicitis may cause a variety of potentially serious complications such as bacterial peritonitis, small bowel obstruction, and abdominal abscess formation. Recently, it was indicated that hyperfibrinogenemia potentially is associated with appendicitis and might be a valuable laboratory marker for acute appendicitis. In a research made by Li et al. [2], plasma fibrinogen levels were significantly increased in patients with acute appendicitis and showed a notable positive correlation with the severity of disease, especially in perforated appendicitis and periappendiceal abscess. To further systematically assess the potential relationship between perforation and fibrinogen levels in a larger group, we performed a retrospective study of 466 children who received appendectomies caused by appendicitis in whom plasma fibrinogen levels also were tested before surgery.
123
Pediatr Surg Int
Materials and methods This study was designed from a pediatric surgery department of an academic teaching hospital. All children under 14 years old admitted between January 2012 and April 2014 were screened in the study. Children were included in the study if they had appendectomies (laparoscopic or open) and laboratory tests performed about 2 h before surgery. Patients were deemed ineligible if they had comorbidity of appendiceal abscess, liver disease, nephrotic syndrome and other diseases that may influence the level of plasma fibrinogen. The initial diagnosis was made by an attending surgeon based on the patient’s history and clinical findings. Either open appendectomy or laparoscopic appendectomy was performed. The preliminary diagnosis of appendiceal perforation was made by the surgeon on the basis of gross appearance, and the ultimate diagnosis was made by a pathologist using histopathological findings observed under a microscope. After a chart review, 466 children were included in the statistical analysis. They were divided into a toddler group (1–3 years old), a preschooler’s group (4–6 years old) and school-age group (7–14 years old) according to age. The relevant preoperative laboratory results included were white blood count (WBC), C-reactive protein (CRP), plasma fibrinogen(FIB). The normal value of WBC and CRP were defined as 4.0/nL to 12.0/nL and less than 8.0 mg/L, respectively. Statistical analysis Statistical analysis was performed using SPSS Version 18.0. Analysis of data distribution was assessed by the Kolmogorov–Smirnov test. For normal distributed data, Student’s t test was used to compare the perforated and non-perforated groups. For non-normal data distribution, the Kruskal–Wallis test was used for comparison. Mean values and SD were calculated for WBC, CRP, fibrinogen levels. In addition, calculation of sensitivity, specificity, negative predictive value, and positive predictive value of fibrinogen, WBC, and CRP as predictors for perforation of the appendix was included in data analysis. Cutoff values were defined as 12/nL for WBC, and 8.0 mg/L for CRP. Statistical significance was set at the 5 %. Pearson Chisquare test was performed to evaluate the statistical significance of the perforation rate difference between the age groups.
Results 466 children who had clinical signs of acute appendicitis and received appendectomies were included in the study.
123
All the children were divided into 3 groups according to age, perforation rate in toddlers group and preschool children were 62 and 46 %, respectively, which were significant higher than the school-age children (31 %) (P = 0.0001) Table 1. Receiver operating characteristic curve analysis for fibrinogen showed that the optimal ratio of sensitivity (0.74) and specificity (0.82) was calculated for a fibrinogen level greater than 5.0 g/L regarding appendiceal perforation (area under receiver operating characteristic curve 0.87) (Fig. 1). Hyperfibrinogenemia ([5.0 g/L) was found in 132 children (74.1 %) of all the perforated children (n = 178). In the toddler group there were 20 children (87.0 %) who had hyperfibrinogenemia in the perforated children (n = 23), in the preschooler’s group there were 51 patients (78.5.0 %) who had hyperfibrinogenemia in the perforated children (n = 65), in the school-age group there were 61 children (67.8 %) who had hyperfibrinogenemia in perforated children (n = 90). The mean fibrinogen level of all patients was 4.89 g/L (SD 1.74 g/L, range 1.94–15 g/L, median 4.61 mg/dL). Children with appendiceal perforation had a mean fibrinogen level of 6.18 g/L (SD 1.83 g/L, range 3.02–15 g/L, median 5.79 g/L), which was significantly higher than non-perforated children (P = 0.0001). In the toddler group, the mean fibrinogen level of perforated children was 6.55 ± 1.46 SD g/L which was significantly higher than non-perforated ones (SD 4.59 ± 1.34 g/L) (P = 0.0001). In the preschoolers group the mean fibrinogen level of perforated children was SD 6.26 ± 1.66 g/L which was significantly higher than non-perforated ones (4.24 ± 1.03 SD g/L) (P = 0.0001). In the school-age group the mean fibrinogen level of perforated children was SD 6.02 ± 2.02 g/L which was significantly higher than non-perforated ones (SD 4.02 ± 1.08 g/L) (P = 0.0001) Fig. 2. Specificity of fibrinogen for the preoperative diagnosis of appendiceal perforation was higher (0.82) compared with WBC (0.25) and CRP (0.34). It was the same with the positive predictive value of fibrinogen for appendiceal perforation (0.72) compared with WBC (0.39) and CRP (0.47). Details of sensitivity, specificity, and predictive values are listed in Table 3. Receiver operating characteristic curve analysis for fibrinogen, WBC, CRP showed that fibrinogen had the largest area under receiver operating characteristic curve (0.87) compared with WBC (0.52) and CRP (0.82). Mean CRP values were 56.5 mg/L (SD 59.9, range 0.5–316 mg/L) in all patients, whereas they were significantly higher in perforated group (96.6 mg/L, SD 66.2, range 1.0–316 mg/L) compared with non-perforated children (P = 0.0001). The mean value of WBC was 16.4/ nL (SD 6.3, range 4–35.8/nL) whereas children in perforated group had a mean of 16.8/nL (SD 6.3, range 4.47–35.8/nL) with no statistical difference compared with non-perforated children (P = 0.250) Tables 2 and 3.
Pediatr Surg Int Table 1 Description perforation rate of each group Group
n
Perforated children
Non-perforated children
Perforation rate (%)
P value
37
23
14
62
0.08a
Preschoolers
141
65
76
46
0.003b
School-age
288
90
198
31
0.000c
Toddler group
a
Represent comparison between toddler group and preschoolers
b
Represent comparison between preschoolers and school-age children
c
Represent comparison between toddler group and school-age children
Fig. 1 Receiver operating characteristic curve analysis for fibrinogen, WBC, and CRP showed fibrinogen had the largest area under receiver operating characteristic curve (0.87) compared with WBC (0.52) and CRP (0.82)
WBCs demonstrated to be a nonspecific marker of inflammation that showed no significant difference between perforated and non-perforated groups.
Discussion Appendiceal perforation in children with acute appendicitis is associated with plenty of postoperative complications. Appendectomy for perforated appendicitis is still a topic of debate because the presence of severe inflammation always changes the normal anatomy and causes dense adherence of the surrounding structures. If a child is highly suspected of having appendicitis, differentiating between perforated from non-perforated appendicitis becomes very important. Emergency operation is strongly recommended for nonperforated appendicitis, however, nonsurgical treatment
may have a lower complication rate for perforated appendicitis [3]. Hence, to avoid delay of a required surgical procedure, high specificity is required in diagnosing perforated appendicitis. Perforation rates in pediatric appendicitis ranges from 23 to 73 % [1]. Lee et al. [4] reported that younger children were more likely to have perforated appendicitis (\5 years). Our results were consistent with those in that report. We observed a higher rate of perforation in toddlers (62 %) and preschool (46 %) children (\6 years) than older children (31 %). Until now, clinical findings such as diffuse peritonitis and board-like rigidity of the abdomen have been decisive factors for the preoperative diagnosis of perforation. The question remains whether an appendicitis is perforated or not until surgery. Although imaging findings such as those obtained from CT and ultrasound are effective for diagnosing appendicitis in children with a relatively high specificity (ranging from 88 to 99 %), sensitivity of ultrasound is poor (ranging from 50 to 100 %) [5–7]. Laboratory values such as WBC and CRP are helpful makers for diagnosing the appendicitis. Nevertheless, both of their specificity are low in predicting appendiceal perforation in our study. Under physiological conditions, plasma concentrations of fibrinogen ranges from 2 to 4 g/L, and fibrinogen has a halflife of approximately 4 days [8]. Nevertheless, in pathological conditions, such as infection, or inflammation after injury, or disease associated with vascular disruption, plasma concentration of fibrinogen increases several times [9]. Thus, fibrinogen is considered as an acute-phase reactant. Meanwhile, increased fibrinogen in the blood is regarded as an indicator for a proinflammatory state and a high-risk marker for developing vascular inflammatory diseases, such as hypertension and atherosclerosis [10]. In most cases, the proinflammatory functions of fibrinogen and its derivative peptides are associated with their ability to bind to and activate a wide range of immune cells through distinct ligand–receptor interactions [9]. Fibrin(ogen) signaling through CD11b/CD18 has been shown to activate proinflammatory pathways, such as NF-jB, which results in local production of inflammatory cytokines, such as TNF-a and IL-1b [11–13]. In vitro studies have shown that fibrinogen can significantly alter WBC function, leading to changes in cell migration, phagocytosis, production of chemokines and
123
Pediatr Surg Int Fig. 2 Box-and-whisker plot showing fibrinogen levels in three groups. There is a significantly higher fibrinogen level in perforated children compared with non-perforated children in each group (toddler group P = 0.0001, preschoolers group P = 0.0001, school-age group P = 0.0001)
Table 2 Details of laboratory values in perforated and non-perforated children in the present study Group
CRP (mg/L)
WBC (9109)
FIB (g/L)
Perforated children (178)
96.58 ? 66.20
16.83 ? 6.26
6.16 ? 1.83
Non-perforated children (288)
31.68 ? 38.67
16.14 ? 6.32
4.10 ? 1.08
P value
0.0001
0.250
0.0001
Table 3 Sensitivity, specificity, positive predictive value, and negative predictive value for WBC, CRP, and fibrinogen Laboratory value
Sensitivity
Specificity
Positive predictive value
Negative predictive value
WBC [ 12
0.76
0.25
0.39
0.63
CRP [ 8
0.94
0.34
0.47
0.90
FIB [ 5 g/L
0.74
0.82
0.72
0.84
To our knowledge, this is the first study using fibrinogen levels to predict perforation in children with acute appendicitis. However, similar studies have not been reported in adult so far, so we are going to do a similar study in adult as the next step. The present study investigated hyperfibrinogenemia as a predictive marker for appendiceal perforation in a large group of 466 patients. We found that patients with appendiceal perforation have significantly higher fibrinogen levels than patients without perforation. In addition, specificity and positive predictive value of fibrinogen were considerably higher in comparison with WBC or CRP. In conclusion, fibrinogen has a relative higher specificity and an acceptable sensitivity as a laboratorial marker for predicting appendiceal perforation compared with WBC and CRP.
References
cytokines, degranulation, and other processes in inflammatory. Many of the effects of fibrinogen on leukocyte activity appear to be mediated by a specific receptor on leukocytes, the integrin receptor aMb2 [14, 15]. In addition to the receptors mentioned above, fibrinogen can either directly or indirectly bind to a number of other receptors, adhesion molecules, and cell-surface proteins that are involved in inflammatory processes. For example, the toll-like receptor 4 (TLR-4) has been implicated with the induction of macrophage activation and the release of several chemokines and cytokines, such as MCP-1, macrophage inflammatory protein-1 (MIP-1) a and b, IL6, TNF-a, and MMP9 [16, 17].
123
1. Sivit CJ (2004) Imaging the child with right lower quadrant pain and suspected appendicitis: current concepts. Pediatr Radiol 34:447–453 2. Li J, Liu Y, Yin W et al (2011) Alterations of the preoperative coagulation profile in patients with acute appendicitis. Clin Chem Lab Med 49(8):1333–1339 3. Henry MC, Gollin G, Islam S et al (2007) Matched analysis of nonoperative management vs immediate appendectomy for perforated appendicitis. J Pediatr Surg 42:19–23 4. Lee SL, Stark R, Yaghoubian A, Shekherdimian S, Kaji A (2011) Does age affect the outcomes and management of pediatric appendicitis? J Pediatr Surg 46:2342–2345 5. Bixby SD, Lucey BC, Soto JA, Theysohn JM,Ozonoff A, Varghese JC (2006) Perforated versus nonperforated acute appendicitis: accuracy of multidetector CT detection. Radiology 241:780–786; erratum 2007;243:302
Pediatr Surg Int 6. Blumfield E, Nayak G, Srinivasan R et al (2013) Ultrasound for differentiation between perforated and nonperforated appendicitis in pediatric patients. AJR 200:957–962 7. Taylor GA (2004) Suspected appendicitis in children: in search of the single best diagnostic test. Radiology 231(2):293–295 8. Tennent GA, Brennan SO, Stangou AJ, O’Grady J, Hawkins PN (2007) Pepys MB Human plasma fibrinogen is synthesized in the liver. Blood 109(5):1971–1974 9. Adams RA, Passino M, Sachs BD, Nuriel T (2004) Akassoglou K Fibrin mechanisms and functions in nervous system pathology. Mol Interv 4(3):163–176 10. Lowe GD (2005) Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 3(8):1618–1627 11. Fan ST, Edgington TS (1993) Integrin regulation of leukocyte inflammatory functions. CD11b/CD18 enhancement of the tumor necrosis factor-alpha responses of monocytes. J Immunol 150(7):2972–2980 12. Perez RL, Roman J (1995) Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells. Implications in pulmonary inflammation. J Immunol 154(4):1879–1887
13. Perez RL, Ritzenthaler JD, Roman J (1999) Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Am J Respir Cell Mol Biol 20(5):1059–1066 14. Flick MJ, Du X, Witte DP, Jirouskova´ M, Soloviev DA, Busuttil SJ et al (2004) Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest 113:1596–1606 15. Tang L, Eaton JW (1993) Fibrin(ogen) mediates acute inflammatory responses to biomaterials. J Exp Med 178:2147–2156 16. Smiley ST, King JA, Hancock WW (2001) Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 167(5):2887–2894 17. Hodgkinson CP, Patel K, Ye S (2008) Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. Thromb Haemost 100(2):301–307
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ORIGINAL ARTICLE
Hyperfibrinogenemia in appendicitis: a new predictor of perforation in children Shaoguang Feng • Peng Wu • Xiaoming Chen
Accepted: 5 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Acute appendicitis is the most common emergency abdominal inflammation requiring operation in children. As an acute-phase protein, plasma fibrinogen always increases with inflammation or tissue necrosis. This had brought about the assumption that hyperfibrinogenemia in patients with appendicitis may have a predictive ability for the preoperative diagnosis of appendiceal. Aim of this retrospective study was to assess the diagnostic value of hyperfibrinogenemia as a preoperative laboratory marker for appendiceal perforation in children with acute appendicitis. Methods We screened 466 children (168 girls, 298 boys, mean age, 7.6 years) with histologically confirmed acute appendicitis who received laparoscopic or open appendectomy between January 2012 and April 2014 in a pediatric surgery department of an academic teaching hospital. A retrospective review of the medical records including appendiceal perforation rate and laboratory results was conducted. Results Mean plasma fibrinogen level of all patients was 4.89 g/L (SD 1.74 g/L, range 1.94–15 g/L, median 4.61 mg/dL). Children with appendiceal perforation had a mean fibrinogen level of 6.18 g/L (SD 1.83 g/L, range 3.02–15 g/L, median 5.79 g/L), which was significantly higher than those with non-perforated children
S. Feng P. Wu Department of Pediatric Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China X. Chen (&) Department of Pediatric Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China e-mail: [email protected]; [email protected]
(P = 0.0001). The specificity of hyperfibrinogenemia for appendiceal perforation was 0.82 in comparison with 0.25 for white blood count (WBC) and 0.34 for C-reactive protein (CRP). Sensitivity was 0.74 compared with 0.76 for WBC and 0.94 for CRP. Conclusion Children with hyperfibrinogenemia and clinical symptoms of appendicitis may be regarded as a higher risk of appendiceal perforation than whose fibrinogen level is normal. Keywords Pediatric Perforated appendicitis Hyperfibrinogenemia Diagnosis
Introduction Acute appendicitis is one of the most common emergencies in children. Rate of appendiceal perforation occurs between 23 and 73 % in children [1]. Appendiceal perforation in children with acute appendicitis may cause a variety of potentially serious complications such as bacterial peritonitis, small bowel obstruction, and abdominal abscess formation. Recently, it was indicated that hyperfibrinogenemia potentially is associated with appendicitis and might be a valuable laboratory marker for acute appendicitis. In a research made by Li et al. [2], plasma fibrinogen levels were significantly increased in patients with acute appendicitis and showed a notable positive correlation with the severity of disease, especially in perforated appendicitis and periappendiceal abscess. To further systematically assess the potential relationship between perforation and fibrinogen levels in a larger group, we performed a retrospective study of 466 children who received appendectomies caused by appendicitis in whom plasma fibrinogen levels also were tested before surgery.
123
Pediatr Surg Int
Materials and methods This study was designed from a pediatric surgery department of an academic teaching hospital. All children under 14 years old admitted between January 2012 and April 2014 were screened in the study. Children were included in the study if they had appendectomies (laparoscopic or open) and laboratory tests performed about 2 h before surgery. Patients were deemed ineligible if they had comorbidity of appendiceal abscess, liver disease, nephrotic syndrome and other diseases that may influence the level of plasma fibrinogen. The initial diagnosis was made by an attending surgeon based on the patient’s history and clinical findings. Either open appendectomy or laparoscopic appendectomy was performed. The preliminary diagnosis of appendiceal perforation was made by the surgeon on the basis of gross appearance, and the ultimate diagnosis was made by a pathologist using histopathological findings observed under a microscope. After a chart review, 466 children were included in the statistical analysis. They were divided into a toddler group (1–3 years old), a preschooler’s group (4–6 years old) and school-age group (7–14 years old) according to age. The relevant preoperative laboratory results included were white blood count (WBC), C-reactive protein (CRP), plasma fibrinogen(FIB). The normal value of WBC and CRP were defined as 4.0/nL to 12.0/nL and less than 8.0 mg/L, respectively. Statistical analysis Statistical analysis was performed using SPSS Version 18.0. Analysis of data distribution was assessed by the Kolmogorov–Smirnov test. For normal distributed data, Student’s t test was used to compare the perforated and non-perforated groups. For non-normal data distribution, the Kruskal–Wallis test was used for comparison. Mean values and SD were calculated for WBC, CRP, fibrinogen levels. In addition, calculation of sensitivity, specificity, negative predictive value, and positive predictive value of fibrinogen, WBC, and CRP as predictors for perforation of the appendix was included in data analysis. Cutoff values were defined as 12/nL for WBC, and 8.0 mg/L for CRP. Statistical significance was set at the 5 %. Pearson Chisquare test was performed to evaluate the statistical significance of the perforation rate difference between the age groups.
Results 466 children who had clinical signs of acute appendicitis and received appendectomies were included in the study.
123
All the children were divided into 3 groups according to age, perforation rate in toddlers group and preschool children were 62 and 46 %, respectively, which were significant higher than the school-age children (31 %) (P = 0.0001) Table 1. Receiver operating characteristic curve analysis for fibrinogen showed that the optimal ratio of sensitivity (0.74) and specificity (0.82) was calculated for a fibrinogen level greater than 5.0 g/L regarding appendiceal perforation (area under receiver operating characteristic curve 0.87) (Fig. 1). Hyperfibrinogenemia ([5.0 g/L) was found in 132 children (74.1 %) of all the perforated children (n = 178). In the toddler group there were 20 children (87.0 %) who had hyperfibrinogenemia in the perforated children (n = 23), in the preschooler’s group there were 51 patients (78.5.0 %) who had hyperfibrinogenemia in the perforated children (n = 65), in the school-age group there were 61 children (67.8 %) who had hyperfibrinogenemia in perforated children (n = 90). The mean fibrinogen level of all patients was 4.89 g/L (SD 1.74 g/L, range 1.94–15 g/L, median 4.61 mg/dL). Children with appendiceal perforation had a mean fibrinogen level of 6.18 g/L (SD 1.83 g/L, range 3.02–15 g/L, median 5.79 g/L), which was significantly higher than non-perforated children (P = 0.0001). In the toddler group, the mean fibrinogen level of perforated children was 6.55 ± 1.46 SD g/L which was significantly higher than non-perforated ones (SD 4.59 ± 1.34 g/L) (P = 0.0001). In the preschoolers group the mean fibrinogen level of perforated children was SD 6.26 ± 1.66 g/L which was significantly higher than non-perforated ones (4.24 ± 1.03 SD g/L) (P = 0.0001). In the school-age group the mean fibrinogen level of perforated children was SD 6.02 ± 2.02 g/L which was significantly higher than non-perforated ones (SD 4.02 ± 1.08 g/L) (P = 0.0001) Fig. 2. Specificity of fibrinogen for the preoperative diagnosis of appendiceal perforation was higher (0.82) compared with WBC (0.25) and CRP (0.34). It was the same with the positive predictive value of fibrinogen for appendiceal perforation (0.72) compared with WBC (0.39) and CRP (0.47). Details of sensitivity, specificity, and predictive values are listed in Table 3. Receiver operating characteristic curve analysis for fibrinogen, WBC, CRP showed that fibrinogen had the largest area under receiver operating characteristic curve (0.87) compared with WBC (0.52) and CRP (0.82). Mean CRP values were 56.5 mg/L (SD 59.9, range 0.5–316 mg/L) in all patients, whereas they were significantly higher in perforated group (96.6 mg/L, SD 66.2, range 1.0–316 mg/L) compared with non-perforated children (P = 0.0001). The mean value of WBC was 16.4/ nL (SD 6.3, range 4–35.8/nL) whereas children in perforated group had a mean of 16.8/nL (SD 6.3, range 4.47–35.8/nL) with no statistical difference compared with non-perforated children (P = 0.250) Tables 2 and 3.
Pediatr Surg Int Table 1 Description perforation rate of each group Group
n
Perforated children
Non-perforated children
Perforation rate (%)
P value
37
23
14
62
0.08a
Preschoolers
141
65
76
46
0.003b
School-age
288
90
198
31
0.000c
Toddler group
a
Represent comparison between toddler group and preschoolers
b
Represent comparison between preschoolers and school-age children
c
Represent comparison between toddler group and school-age children
Fig. 1 Receiver operating characteristic curve analysis for fibrinogen, WBC, and CRP showed fibrinogen had the largest area under receiver operating characteristic curve (0.87) compared with WBC (0.52) and CRP (0.82)
WBCs demonstrated to be a nonspecific marker of inflammation that showed no significant difference between perforated and non-perforated groups.
Discussion Appendiceal perforation in children with acute appendicitis is associated with plenty of postoperative complications. Appendectomy for perforated appendicitis is still a topic of debate because the presence of severe inflammation always changes the normal anatomy and causes dense adherence of the surrounding structures. If a child is highly suspected of having appendicitis, differentiating between perforated from non-perforated appendicitis becomes very important. Emergency operation is strongly recommended for nonperforated appendicitis, however, nonsurgical treatment
may have a lower complication rate for perforated appendicitis [3]. Hence, to avoid delay of a required surgical procedure, high specificity is required in diagnosing perforated appendicitis. Perforation rates in pediatric appendicitis ranges from 23 to 73 % [1]. Lee et al. [4] reported that younger children were more likely to have perforated appendicitis (\5 years). Our results were consistent with those in that report. We observed a higher rate of perforation in toddlers (62 %) and preschool (46 %) children (\6 years) than older children (31 %). Until now, clinical findings such as diffuse peritonitis and board-like rigidity of the abdomen have been decisive factors for the preoperative diagnosis of perforation. The question remains whether an appendicitis is perforated or not until surgery. Although imaging findings such as those obtained from CT and ultrasound are effective for diagnosing appendicitis in children with a relatively high specificity (ranging from 88 to 99 %), sensitivity of ultrasound is poor (ranging from 50 to 100 %) [5–7]. Laboratory values such as WBC and CRP are helpful makers for diagnosing the appendicitis. Nevertheless, both of their specificity are low in predicting appendiceal perforation in our study. Under physiological conditions, plasma concentrations of fibrinogen ranges from 2 to 4 g/L, and fibrinogen has a halflife of approximately 4 days [8]. Nevertheless, in pathological conditions, such as infection, or inflammation after injury, or disease associated with vascular disruption, plasma concentration of fibrinogen increases several times [9]. Thus, fibrinogen is considered as an acute-phase reactant. Meanwhile, increased fibrinogen in the blood is regarded as an indicator for a proinflammatory state and a high-risk marker for developing vascular inflammatory diseases, such as hypertension and atherosclerosis [10]. In most cases, the proinflammatory functions of fibrinogen and its derivative peptides are associated with their ability to bind to and activate a wide range of immune cells through distinct ligand–receptor interactions [9]. Fibrin(ogen) signaling through CD11b/CD18 has been shown to activate proinflammatory pathways, such as NF-jB, which results in local production of inflammatory cytokines, such as TNF-a and IL-1b [11–13]. In vitro studies have shown that fibrinogen can significantly alter WBC function, leading to changes in cell migration, phagocytosis, production of chemokines and
123
Pediatr Surg Int Fig. 2 Box-and-whisker plot showing fibrinogen levels in three groups. There is a significantly higher fibrinogen level in perforated children compared with non-perforated children in each group (toddler group P = 0.0001, preschoolers group P = 0.0001, school-age group P = 0.0001)
Table 2 Details of laboratory values in perforated and non-perforated children in the present study Group
CRP (mg/L)
WBC (9109)
FIB (g/L)
Perforated children (178)
96.58 ? 66.20
16.83 ? 6.26
6.16 ? 1.83
Non-perforated children (288)
31.68 ? 38.67
16.14 ? 6.32
4.10 ? 1.08
P value
0.0001
0.250
0.0001
Table 3 Sensitivity, specificity, positive predictive value, and negative predictive value for WBC, CRP, and fibrinogen Laboratory value
Sensitivity
Specificity
Positive predictive value
Negative predictive value
WBC [ 12
0.76
0.25
0.39
0.63
CRP [ 8
0.94
0.34
0.47
0.90
FIB [ 5 g/L
0.74
0.82
0.72
0.84
To our knowledge, this is the first study using fibrinogen levels to predict perforation in children with acute appendicitis. However, similar studies have not been reported in adult so far, so we are going to do a similar study in adult as the next step. The present study investigated hyperfibrinogenemia as a predictive marker for appendiceal perforation in a large group of 466 patients. We found that patients with appendiceal perforation have significantly higher fibrinogen levels than patients without perforation. In addition, specificity and positive predictive value of fibrinogen were considerably higher in comparison with WBC or CRP. In conclusion, fibrinogen has a relative higher specificity and an acceptable sensitivity as a laboratorial marker for predicting appendiceal perforation compared with WBC and CRP.
References
cytokines, degranulation, and other processes in inflammatory. Many of the effects of fibrinogen on leukocyte activity appear to be mediated by a specific receptor on leukocytes, the integrin receptor aMb2 [14, 15]. In addition to the receptors mentioned above, fibrinogen can either directly or indirectly bind to a number of other receptors, adhesion molecules, and cell-surface proteins that are involved in inflammatory processes. For example, the toll-like receptor 4 (TLR-4) has been implicated with the induction of macrophage activation and the release of several chemokines and cytokines, such as MCP-1, macrophage inflammatory protein-1 (MIP-1) a and b, IL6, TNF-a, and MMP9 [16, 17].
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