American Journal of Emergency Medicine 35 (2017) 6670

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American Journal of Emergency Medicine

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Original Contribution

Diagnostic accuracy of brinogen to differentiate appendicitis from

nonspecic abdominal pain in children
Marcos Prada-Arias, MD, PhD a,e,, Jos Luis Vzquez, MD, PhD b,
ngel Salgado-Barreira, PhD c,e, Javier Gmez-Veiras, MD a,
Margarita Montero-Snchez, MD, PhD a,e, Jos Ramn Fernndez-Lorenzo, MD, PhD d,e
a
Department of Pediatric Surgery, University Hospital lvaro Cunqueiro, Carretera Clara Campoamor, 341, 36312 Vigo, Spain
b
Department of Radiology, University Hospital lvaro Cunqueiro, Carretera Clara Campoamor, 341, 36312 Vigo, Spain
c
Unit Supporting Research, University Hospital lvaro Cunqueiro, Carretera Clara Campoamor, 341, 36312 Vigo, Spain
d
Department of Pediatrics, University Hospital lvaro Cunqueiro, Carretera Clara Campoamor, 341, 36312 Vigo, Spain
e
Health Research Institute Galicia Sur, Carretera Clara Campoamor, 341, 36312 Vigo, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Aim: The aim of this study was to assess the diagnostic accuracy of the biomarker brinogen (FB), along with the
Received 23 July 2016 more traditional markers white blood cell count (WBC), absolute neutrophil count (ANC), and C-reactive protein
Received in revised form 7 September 2016 (CRP), to discriminate appendicitis from nonspecic abdominal pain (NSAP) in children.
Accepted 3 October 2016 Methods: We prospectively evaluated all children aged 5 to 15 years admitted for suspected appendicitis at an
academic pediatric emergency department during 2 years. Diagnostic accuracy of FB (prothrombin time
derived method), WBC, ANC, and CRP was assessed by the area under the curve (AUC) of the receiver operating
characteristic curve.
Results: A total of 275 patients were enrolled in the study (143 NSAP, 100 uncomplicated appendicitis, and 32
complicated appendicitis). WBC and ANC had a moderate diagnostic accuracy for appendicitis vs NSAP (WBC:
AUC 0.79, ANC: AUC 0.79). FB and CPR had a poor diagnostic accuracy for appendicitis vs NSAP (FB: AUC 0.63,
CRP: AUC 0.64) and a good diagnostic accuracy for complicated vs uncomplicated appendicitis (FB: AUC 0.86,
CRP: AUC 0.90). All inammatory markers had a good diagnostic accuracy for complicated appendicitis vs NSAP.
Conclusions: WBC and ANC are useful inammatory markers to discriminate appendicitis from NSAP. FB and CRP
are not very useful to discriminate appendicitis from NSAP, but they discriminate properly complicated from
uncomplicated appendicitis and NSAP, with a similar diagnostic accuracy. In a child with suspected appendicitis,
a plasma FB level (prothrombin timederived method) N520 mg/dL is associated to an increased likelihood of
complicated appendicitis.
2016 Elsevier Inc. All rights reserved.

1. Introduction
Appendicitis is the most common acute surgical condition of the
abdomen in children. It is diagnosed in up to 10% of children presenting
with acute abdominal pain at the emergency department [1]. A compati-
ble clinical history and physical examination remain the cornerstone of
diagnosis. Other diagnostic tools such as inammatory markers, imaging
studies including ultrasonography (US) and computed tomography, and
clinical prediction rules and protocols signicantly help in the diagnostic
Funding source declaration: This research did not receive any specic grant from
funding agencies in the public, commercial, or not-for-prot sectors.
Corresponding author at: Department of Pediatric Surgery, University Hospital lvaro
Cunqueiro, Carretera de Clara Campoamor, 341, 36312 Vigo, Spain. Tel.: +34 986811111,
+34 64809747.
E-mail address: marcospradaarias@gmail.com (M. Prada-Arias).
process, increasing both efciency and accuracy [2]. Despite all these
diagnostic advances, initial evaluation misdiagnosis rates in children
can reach up to 30% mainly because of the variable and nonspecic pre-
sentation of the disease and the wide differential diagnosis of abdomi-
nal pain in children. Misdiagnosis is associated with high rates of
perforation (12%-38%), leading to signicant morbidity and negative
appendectomy (2%-30%) [3,4].
Diagnostic accuracy of inammatory markers to discriminate appen-
dicitis is limited because they are increased in many abdominal pain
disorders [2]. White blood cell count (WBC), absolute neutrophil count
(ANC), and C-reactive protein (CRP) are the most studied and used in
clinical practice. Other potential markers of appendicitis have been
evaluated, such as procalcitonin [5], bilirubin [6], calprotectin [7], or
interlekin-6 [8], but for now have not been found any more useful [9].
Fibrinogen (FB) has been reported recently as a useful biomarker in
the diagnosis of appendicitis because it is an important inammatory
modulator [10,11].

http://dx.doi.org/10.1016/j.ajem.2016.10.003
0735-6757/ 2016 Elsevier Inc. All rights reserved.
 M. Prada-Arias et al. / American Journal of Emergency Medicine 35 (2017) 6670
Because nonspecic abdominal pain (NSAP) is the most common
diagnosis on discharge following admission for abdominal pain in child-
hood and it is the most common process that requires differential diag-
nosis with appendicitis in clinical practice [12-14], we compare
inammatory markers only in these groups of patients.
The aim of this prospective study was to assess the diagnostic accu-
racy of the biomarker FB, along with the more traditional inammatory
markers WBC, ANC, and CRP, to differentiate appendicitis from NSAP
in children.
2. Methods
This prospective, observational study was conducted at a tertiary
academic pediatric emergency department (University Hospital of
Vigo, Spain), enrolling subjects aged 5 to 15 years admitted for
suspected appendicitis between January 1, 2013, and December 31,
2014. We selected cases of NSAP and appendicitis according to inclusion
and exclusion criteria. Inclusion criteria were clinical suspicion of
appendicitis; laboratory studies including WBC, ANC, CRP, and FB (pro-
thrombin timederived method); and abdominal US requested for
suspected appendicitis. Exclusion criteria were age less than 5 years
(appendicitis has a different presentation and evolution in this age
group); duration of symptoms of less than 6 hours or more than
72 hours (abdominal pain cases less than 6 hours are generally under
observation without performing laboratory tests, and cases longer
than 72 hours rarely require differential diagnosis between NSAP and
appendicitis in clinical practice); hematologic, oncologic, hepatic, infec-
tious, or inammatory disease detected or present in the previous
month to admission; anticoagulant, antibiotic, and anti-inammatory
medication in the previous month to admission (these diseases and
medications can alter inammatory markers values and lead to biased
results); more than 12 hours of interval between laboratory tests and
appendectomy (to get a suitable correlation between inammatory
markers values and type of appendicitis); unclear histological report
(focal, incipient, or congestive appendicitis); and nonoperatively
managed appendicitis cases (histopathological examination of the
appendix is not available). Diagnosis of NSAP was performed in cases
of nonspecic detection of disease, including abdominal US without
specic ndings in all cases and no antibiotic treatment in the month
following diagnosis, to avoid including undetected appendicitis or infec-
tious disease cases resolved by the treatment. The patient's parents or
legal guardians gave consent to access their data for research purposes.
This study was approved by the Clinical Research Ethical Committee of
Galicia (Spain) (2013/361).
2.1. Patient variables
We collected several variables including age; sex; duration of symp-
toms; WBC, ANC, CRP, and FB levels; and appendicitis type (suppurative,
gangrenous, and perforated). The criterion standard for appendicitis diag-
nosis was the histological report in suppurative and gangrenous appendi-
citis and the surgical report in perforated appendicitis. Suppurative
appendicitis was diagnosed by the presence of neutrophilic inltrate
within the muscularis propria; and gangrenous appendicitis, by the
presence of appendix wall necrosis [15]. Perforated appendicitis was
diagnosed by the existence of a hole in the appendix or a fecalith in the
peritoneal cavity [16]. Suppurative appendicitis was considered uncom-
plicated, while gangrenous appendicitis and perforated appendicitis
were considered complicated. A 30-day telephone follow-up since admis-
sion was completed for all cases discharged with diagnosis of NSAP to
assess criteria.
We measured WBC and ANC by an automated hematology analyzer
(Advia 120 Hematology System, Siemens). Normal reference value for
WBC (10 9/L) is 3.5-11.0 and for ANC (10 9/L) is 2.0-7.0. Serum CRP
levels were measured by immunoturbidimetric assay (Synchron Unicel
DxC 600i Analyzer, Beckman Coulter). Normal reference values for CRP
67
(mg/L) are 0-3. Plasma FB levels were measured by prothrombin time
derived method by turbidimetric assay (ACL-TOP 500 Coagulometer,
Izasa) using Recombiplastin 2 g (Instrumentation Laboratory) as re-
agent. Normal reference values for FB (mg/dL) are 150-600.
2.2. Statistical analysis
Statistical analysis was performed using SPSS 19.0 (SPSS Inc, Chicago,
IL, 2010) for Windows. We performed descriptive and univariate
analysis using Student t test or Mann-Whitney U test to compare 2
groups, and analysis of variance or Kruskal-Wallis tests to compare
more than 2 groups, according to variables normality and variances
homogeneity, to the quantitative variables. 2 test was used in the
qualitative variables to compare different groups. P values b .05 were
considered as statistically signicant. We assessed diagnostic accuracy
of inammatory variables by the area under the curve (AUC) of the re-
ceiver operating characteristic (ROC) curve using the optimal ratio of
sensitivity and specicity as the criterion for selecting the best cutoff
value (CV) corresponding to the variable value with greater discrimina-
tion power between different groups.
3. Results
During the study period, 764 patients were evaluated for suspected
appendicitis. NSAP and appendicitis were the most frequent diagnosis
with 327 (42%) and 273 (36%) cases, respectively (Table 1). Following
the inclusion and exclusion criteria, 275 patients were enrolled in the
study composed of 143 NSAP and 132 appendicitis cases; there were
100 cases of uncomplicated appendicitis (suppurative appendicitis)
and 32 cases of complicated appendicitis (9 gangrenous and 23 perfo-
rated appendicitis).
Descriptive and univariate analyses of all variables are shown in
Tables 2 and 3.
Analysis showed statistically signicant differences in sex but not in
age or duration of symptoms between the NSAP and appendicitis
groups. Analysis of NSAP, uncomplicated appendicitis, and complicated
appendicitis groups showed statistically signicant differences in dura-
tion of symptoms, with a mean increase according to the severity of
disease and without cases of complicated appendicitis with duration of
symptoms of less than 12 hours. Analysis of inammatory variables in re-
lation to NSAP and appendicitis groups showed statistically signicant
differences in all cases (P b .001). Analysis of inammatory variables in
relation to NSAP, uncomplicated appendicitis, and complicated appendi-
citis showed statistically signicant differences in all cases (P b .05),
except the analysis of CRP and FB in relation to NSAP and uncomplicated
appendicitis groups (P N .05).
The AUCs of ROC curves of inammatory variables in the different
groups of patients are shown in Tables 4 and 5.
Our results showed that WBC and ANC had a moderate diagnostic
accuracy for appendicitis vs NSAP (WBC: AUC 0.79 with CV in 10.5
109/L, ANC: AUC 0.79 with CV in 7.5 109/L) (Fig. 1), with a moderate
diagnostic accuracy for uncomplicated appendicitis vs NSAP (WBC:
AUC 0.77, ANC: AUC 0.77), a good diagnostic accuracy for complicated
appendicitis vs NSAP (WBC: AUC 0.85 with CV in 14.7 10 9/L, ANC:
Table 1
Cases of suspected appendicitis (2013-2014)
NSAP 327 (42.8%)
Appendicitis 273 (35.7%)
Mesenteric adenitis 35 (4.5%)
Acute gastroenteritis 24 (3.1%)
Urinary tract infection 17 (2.2%)
Ovarian cyst 14 (1.8%)
Respiratory tract infection 11 (1.4%)
Others 63 (8.2%)
Total 764 (100%)
68 M. Prada-Arias et al. / American Journal of Emergency Medicine 35 (2017) 6670

Table 2 to their frequent presence in many abdominal pain disorders in children

Descriptive and univariate analysis of variables in NSAP and appendicitis groups [22]. WBC and ANC are considered elevated, according to the diagnosis
Variable NSAP Appendicitis P value of appendicitis, when their values reach or exceed 10.0 10 9/L and 7.5
(n = 143) (n = 132) 109/L, respectively [23]. Our study reveals similar gures regarding di-
Sex, male/female (relation) 60/83 (1:1.4) 93/39 (2.4:1) b.01b agnostic accuracy, showing that WBC and ANC have a moderate power
Age, mean (y) SD 10.4 2.5 9.9 2.5 .152a of discrimination between appendicitis and NSAP.
DS (h) SD 25.8 16.9 24.2 15.9 .406a CRP was the rst acute phase protein to be described and is a sensi-
WBC (109/L) mean SD 10.94 5.26 15.47 3.99 b.001a
tive marker of inammation and tissue damage. Its synthesis starts
ANC (109/L) mean SD 7.97 5.25 12.51 3.93 b.001a
CRP (mg/L) mean SD 15.8 22.0 37.1 52.1 b.001a within 4-6 hours of stimulation, doubling its concentration every 8
FB (mg/dL) mean SD 444 88 500 120 b.001a hours, so that blood levels rise signicantly from 12 to 24 hours [24].
DS, duration of symptoms.
Its sensitivity and specicity for the diagnosis of appendicitis vary wide-
a
Student t test. ly in the literature, with gures ranging from 58% to 100% and 28% to
b
2 test. 93%, respectively [20,25,26]. CRP is less sensitive than WBC and ANC
in the rst 24 hours from onset of symptoms; however, its sensitivity
AUC 0.85 with CV in 11.3 109/L) (Fig. 2), and a poor diagnostic accu- is higher when the evolution is 24-48 hours [26]. CRP does not accurate-
racy for complicated vs uncomplicated appendicitis (WBC: AUC 0.62, ly discriminate appendicitis, especially in early stages of the disease, be-
ANC: AUC 0.65) (Fig. 3). CRP and FB had a poor diagnostic accuracy for cause its values overlap with values present in other frequent processes
appendicitis vs NSAP (CRP: AUC 0.64, FB: AUC 0.63) (Fig. 1), with a in children, but it is useful to differentiate complicated from uncompli-
poor diagnostic accuracy for uncomplicated appendicitis vs NSAP cated cases [20,27]. Different studies have shown that uncomplicated
(CRP: AUC 0.56, FB: AUC 0.55), a good diagnostic accuracy for compli- appendicitis is associated with CRP values of 10-50 mg/L, whereas in
cated appendicitis vs NSAP (CRP: AUC 0.92 with CV in 30 mg/L, FB: complicated appendicitis, the CRP values are usually greater than 50
AUC 0.89 with CV in 520 mg/dL) (Fig. 2), and a good diagnostic accuracy mg/L [28]. Our study showed that the diagnostic accuracy of CRP is
for complicated vs uncomplicated appendicitis (CRP: AUC 0.90 with CV poor to discriminate appendicitis from NSAP but good to discriminate
in 30.0 mg/L, FB: AUC 0.86 with CV in 520 mg/dL) (Fig. 3). complicated appendicitis from uncomplicated appendicitis and NSAP.
According to our data, a CRP value N30.0 mg/L is associated to an in-
4. Discussion creased likelihood of complicated appendicitis, similar to reported
values in the literature [29].
The term NSAP refers to abdominal pain for which organic pathology FB, clotting factor I, is a plasma glycoprotein with proinammatory
is not the cause suspected by the attending medical professional [13]. It functions associated with its ability to bind to receptors and activate
is a diagnosis of exclusion, identifying a nonspecic syndrome that several types of immune cells involved in the inammatory response
is self-limiting and does not recur [12]. NSAP is a safe diagnosis in [30]. It is an inammatory modulator and induces specic functions in
pediatric population because only 1.6%-5.8% of cases will be diagnosed different diseases [31]. It is reduced in some hereditary diseases, liver
of a specic disease and the risk of missing appendicitis is low. Never- disease (reduced synthesis), consumption coagulopathy, and situations
theless, NSAP is the most common diagnosis on discharge following ad- of thrombolytic therapy or hemodilution and is increased in some phys-
mission for abdominal pain in childhood and the most common process iological situations (pregnancy, menopause, or intense physical exer-
that requires differential diagnosis with appendicitis in clinical practice cise) and pathological processes such as trauma, vascular damage,
[12,13]. In our study, NSAP was the main diagnosis (42%) of all cases ad- infection, or inammation, being considered as an acute phase reactant
mitted for suspected appendicitis. [30]. In clinical practice, plasma FB levels are measured with functional
We elected to exclude from the study children younger than 5 years tests using the Clauss or the prothrombin timederived methods. The
because NSAP and appendicitis are rare diagnoses in these patients Clauss method is not a direct measurement of plasma FB but rather an
[14] and appendicitis has a different presentation and evolution in this estimate based on thrombin time, usually performed by an automatic
age group, probably in relation to a different pathophysiology of the coagulometer. It is the test generally used in clinical practice, although
disease [17]. it takes a long time. Prothrombin timederived method is an estimate
NSAP has no sex predominance [13,12], but appendicitis is most performed by a photo-optical coagulometer, according to the changes
prevalent in males, occurring at a ratio of 1.5-1.9:1 [4], as reected in the in absorbance, while calculating the prothrombin time. The advantages
largest proportion of males in our group of appendicitis (relation 2.4:1). of this method are its speed and cost savings. The level of FB obtained by
WBC and ANC are elevated in 73%-96% of patients with appendicitis the prothrombin timederived method is signicantly higher than that
[18], and they seem to be more useful in the rst 24 hours of evolution by the Clauss method under certain conditions that affect clotting, such
of disease in relation to the early neutrophil activation (3-6 hours) asso- as coagulopathies, hemolysis, liver and kidney diseases, acute phase re-
ciated to inammatory processes [19]. Their sensitivity and specicity actions, and anticoagulant or thrombolytic treatments. This variability
reported in the literature are variable, with gures ranging from 55% between tests is due to several reasons such as the presence of brin
to 89% and 43% to 66%, respectively [20,21]. This low specicity is due degradation products; the heterogeneity of FB; the differences in the

Table 3
Univariate analysis of variables in NSAP, uncomplicated appendicitis, and complicated appendicitis groups

Variable NSAP (n = 143) Uncomplicated App (n = 100) Complicated App (n = 32) P value

Mean SD 95% CI Range Mean SD 95% CI Range Mean SD 95% CI Range

Age (y) 10.4 2.5 10.0-10.8 5-14 9.9 2.5 9.4-10.4 5-14 10.2 2.8 9.2-11.2 5-14 .296a
DS (h) 25.8 16.9 23.0-28.6 6-72 19.8 12.3 17.3-22.2 6-72 37.9 18.3 31.3-44.5 12-72 b.001b
WBC (109/L) 10.9 5.3 10.1-11.8 3.2-32.8 15.0 3.8 14.2-15.7 4.8-22.7 17.0 4.1 15.5-18.5 8.3-26.7 b.001a
ANC (109/L) 8.0 5.2 7.1-8.8 1.6-28.9 12.0 3.7 11.2-12.6 2.6-19.9 14.4 4.1 12.9-15.8 7.4-24.4 b.001b
CRP (mg/L) 15.8 22.0 12.2-19.5 0.20-137.0 18.8 25.8 13.7-23.9 0.20-177.5 94.3 69.9 69.1-119.5 12.2-253.8 b.001b
FB (mg/dL) 444 88 429-458 263-659 464 102 443-484 282-771 613 102 576-649 446-796 b.001a

App, appendicitis.
a
ANOVA test.
b
Kruskal-Wallis test.
 M. Prada-Arias et al. / American Journal of Emergency Medicine 35 (2017) 6670 69

Table 4
AUC of ROC curves and the best CVs of inammatory variables to discriminate appendicitis from NSAP and uncomplicated appendicitis from NSAP

Variable Appendicitis/NSAP Uncomplicated App/NSAP

AUC 95% CI CV Sn % Sp % AUC 95% CI CV Sn % Sp %

WBC (109/L) 0.79 0.74-0.85 10.5 89.4 57.3 0.77 0.71-0.83 10.5 87.0 57.3
ANC (109/L) 0.79 0.73-0.84 7.5 90.2 60.1 0.77 0.71-0.83 7.5 88.0 61.1
CRP (mg/L) 0.64 0.58-0.71 25.5 43.2 79.7 0.56 0.49-0.63
FB (mg/dL) 0.63 0.57-0.70 510 43.9 79.7 0.55 0.48-0.62

Sn, sensitivity; Sp, specicity.

Table 5
AUC of ROC curves and best CVs of inammatory variables to discriminate complicated appendicitis from NSAP and complicated from uncomplicated appendicitis

Variable Complicated App/NSAP Complicated/uncomplicated App

AUC 95% CI CV Sn % Sp % AUC 95% CI CV Sn % Sp %

WBC (109/L) 0.85 0.78-0.91 14.7 81.3 82.5 0.62 0.51-0.73 14.7 81.3 49.0
ANC (109/L) 0.85 0.80-0.91 11.3 81.3 79.0 0.65 0.54-0.75 11.3 81.3 44.0
CRP (mg/L) 0.92 0.87-0.96 30.0 87.5 81.8 0.90 0.85-0.96 30.0 87.5 76.0
FB (mg/dL) 0.89 0.84-0.95 520 84.4 81.1 0.86 0.79-0.92 520 84.4 72.0

individual properties of the methods; and the different qualities of the
reagents, calibrators, and analyzers. This variability does not allow
establishing a common reference range for both tests and makes it
impossible to develop an algorithm to compensate for the specic
differences; thus, it is very important to specify the method used for
each patient or group of patients and its range reference [32].
The utility of FB in the diagnosis of appendicitis has been barely
studied, with only 3 studies reported in the literature, only 1 of them
in children, concluding that it might be useful because of its positive
correlation with the severity of the disease, being especially useful to
differentiate uncomplicated from perforated appendicitis [10,11,33]. In
our study, the diagnostic accuracy of FB was poor to discriminate appen-
dicitis from NSAP, but it was good at discriminating complicated appen-
dicitis from uncomplicated appendicitis and NSAP, with the best CV of
520 mg/dL.
5. Limitations
Limitations of this study include the following: (a) Histopathological
examination of the appendix, considered the reference standard for
appendicitis diagnosis, is not available for patients with NSAP (partial
verication bias or workup bias) [34,35]. Nonoperated patients, who
did not develop appendicitis during follow-up, were assumed to be
cases without disease, but epidemiological and clinical imaging studies
have shown that spontaneous resolution of disease is possible [36];
therefore, it cannot be excluded that some cases of NSAP were actually
self-limiting uncomplicated appendicitis [34]. (b) The heterogeneity
of the NSAP group, with possible inclusion of undetected specic disor-
ders, including unresolved cases of uncomplicated appendicitis (spec-
trum bias). NSAP was only diagnosed in cases of nonspecic detection
of disease, including abdominal US without specic ndings on admis-
sion, and no antibiotic treatment in the month following diagnosis. (c)
Period of time from the blood sample to the appendectomy (disease
progression bias). To reduce this bias, we excluded from the study
those cases where this time period exceeded 12 hours. (d) Undetected
processes that could modify FB level (spectrum bias). Disorders or treat-
ments that could potentially modify FB level were excluded to minimize
this bias. (e) The inherent variability of analytic methods (measurement
bias). All inammatory markers determinations were performed in the
laboratory of our hospital using the same methods and analyzers [35].

Fig. 2. ROC curves for WBC, ANC, CRP, and FB to discriminate complicated appendicitis
Fig. 1. ROC curves for WBC, ANC, CRP, and FB to discriminate appendicitis from NSAP. from NSAP.
70 M. Prada-Arias et al. / American Journal of Emergency Medicine 35 (2017) 6670
Fig. 3. ROC curves for WBC, ANC, CRP, and FB to discriminate complicated from
uncomplicated appendicitis.
6. Conclusions
WBC and ANC are useful inammatory markers to discriminate
appendicitis from NSAP, but they do not discriminate properly compli-
cated from uncomplicated appendicitis. FB and CRP are not very useful
to discriminate appendicitis from NSAP, but they discriminate properly
complicated from uncomplicated appendicitis and NSAP, with a similar
diagnostic accuracy. In a child with suspected appendicitis, a plasma FB
level (prothrombin timederived method) N520 mg/dL is associated
with an increased likelihood of complicated appendicitis. In the future,
it will be interesting to test the diagnostic value of combinations of
these markers.
Conict of interest
The authors declare that they have no conict of interest.
Author declaration
All authors have seen and approved the nal version of the manu-
script being submitted, and they warrant that the article is the authors'
original work, has not received prior publication, and is not under con-
sideration for publication elsewhere.
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