International Journal of Surgery 40 (2017) 155e162

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International Journal of Surgery

journal homepage: www.journal-surgery.net

Review

How to diagnose an acutely inflamed appendix; a systematic review of

the latest evidence
S.A. Kabir a, *, S.I. Kabir b, R. Sun a, Sadaf Jafferbhoy a, Ahmed Karim a
a
Department of Surgery, Worcester Royal Hospital, UK
b
Department of Surgery, Oxford University Hospitals NHS Trust, UK

h i g h l i g h t s

! Acute appendicitis is the most common condition that presents to hospitals with an acute abdomen.
! A delay or mis-diagnosis of appendicitis can result in severe complications.
! Raised Alvarado scores and laboratory markers all contribute to the suspicion of appendicitis.
! The use of USS-CT pathways or even USS-MRI pathways increases diagnostic certainty without always having to expose unclear cases to radiation.
! The alternative use of repeat USS may reach a sensitivity of 100%.

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

Article history: Acute appendicitis is the most common condition that presents with an acute abdomen needing
Received 1 December 2016 emergency surgery. Despite this common presentation, correctly diagnosing appendicitis remains a
Received in revised form challenge as clinical signs or positive blood results can be absent in 55% of the patients.
11 February 2017
The reported proportion of missed diagnoses of appendicitis ranges between 20% and 40%. A delay or
Accepted 4 March 2017
mis-diagnosis of appendicitis can result in severe complications such as perforation, abscess formation,
Available online 6 March 2017
sepsis, and intra-abdominal adhesions.
Literature has shown that patients who had a negative appendectomy suffer post-op complications
Keywords:
Diagnosis of appendicitis
and infections secondary to hospital stays; there have even been reported cases of fatality.
ALVARADO score It is therefore crucial that timely and accurate diagnosis of appendicitis is achieved to avoid compli-
Imaging and appendicitis cations of both non-operating as well as unnecessary surgical intervention.
CT and appendicitis The aim of this review is to systematically report and analyse the latest evidence on the different
USS and appendicitis approaches used in diagnosing appendicitis. We include discussions of clinical scoring systems, labo-
Laboratory markers in appendicitis ratory tests, latest innovative bio-markers and radiological imaging.
Novel markers in appendicitis © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction proportion of missed diagnoses ranges between 20% and 40%;

Acute appendicitis is the most common condition that presents
with an acute abdomen needing emergency surgery. Within the
general population, the lifetime incidence is estimated to be 7%
with a male to female ratio of three to two until the fourth decade
of age [1,2].
Despite this common presentation, correctly diagnosing
appendicitis remains a challenge as clinical signs or positive blood
results can be absent in 55% of the patients [3]. The reported
* Corresponding author. 10 Ashton Court, Worcester, WR53FR, UK.
E-mail address: adnankabir58@hotmail.com (S.A. Kabir).
negative appendectomy rates are reported to range between 10%
and 34% [4e8].
A delay or mis-diagnosis of appendicitis can result in severe
complications such as perforation, abscess formation, sepsis, and
intra-abdominal adhesions. It is also the most common cause of
litigation and hospital payoff in America [9].
Flum et al. [10] showed that patients who had a negative ap-
pendectomy suffer post-op complications and infections secondary
to hospital stays; there have even been reported cases of fatality. It
is therefore crucial that timely and accurate diagnosis of appendi-
citis is achieved to avoid complications of both non-operating as
well as unnecessary surgical intervention.
The aim of this review is to systematically report and analyse the

http://dx.doi.org/10.1016/j.ijsu.2017.03.013
1743-9191/© 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
156 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162
latest evidence on the different approaches used in diagnosing
appendicitis. We include discussions of clinical scoring systems,
laboratory tests, latest innovative bio-markers and radiological
imaging.
2. Methods
This systematic review was carried out using the AMSTAR
(Assessment of Multiple Systematic Reviews) measurement tool
[11]. A literature search was performed using multiple electronic
search engines: PUBMED, MEDLINE and Cochrane Database. We
included literature from January 2000 until November 2015.
The key search phrases used were: diagnosis of appendicitis;
ALVARADO score; imaging and appendicitis; CT and appendicitis;
USS and appendicitis; laboratory markers in appendicitis; novel
markers in appendicitis. The keywords were used in mixed com-
binations to generate the maximum number of articles. The refer-
ences of relevant articles were also screened and included if
relevant. Combination, truncation and explode functions were
used.
All studies from our searches were included with no restrictions
on study design. Data was collected categorically for author of the
study, date of publication, study design and clinical parameters
assessed.
The following commonly used variables were reviewed: clinical
symptoms, scoring methods, blood markers and imaging. Other
less commonly used investigation modalities such as MRI scans and
novel markers were also reviewed.
The following inclusion and exclusion criteria were applied:
1. The study included ultimate diagnoses of appendicitis.
2. Inclusion of at least one of our outcome measures mentioned
above.
3. Studies of only human subjects.
4. Publication language was English.
Fig. 1. PRISMA flow diagram [12].
The literature search revealed 3305 articles. Two independent
researchers screened title and abstracts, 3222 articles were
considered irrelevant. A third independent reviewer reviewed
equivocal cases. After applying inclusion and exclusion criteria, a
total of 58 studies were selected for final review. Our selections
were based on the PRISMA Flow methodology (Fig. 1). Our included
studies comprised of randomized controlled trials, meta-analyses,
systematic reviews, retrospective studies, case series and case
reports.
2.1. The role of Alvarado scoring system in diagnosis appendicitis
The Alvarado scoring system was developed in Philadelphia in
the mid 80s to estimate the possibility of appendicitis in patients
presenting with suspect abdominal pain [13]. The original study
was based on retrospective analysis of 305 patients. They included
analysis of clinical history, examination and laboratory tests. The
study found eight predictive factors of importance in the diagnosis
of appendicitis, and each factor is scored out of 2 (Table 1). There is
a difference in opinion on management plans when a patient scores
seven or eight. Many recommend repeated examinations and blood
tests (the ‘watch and wait’ method), while others encourage the use
of early imaging or even diagnostic laparoscopy.
The original Alvarado study reports 81% sensitivity and 74%
specificity; subsequent studies by other researchers have shown
higher sensitivity rates and lower specificity rates. This has gained
support for the use of the scoring system in “ruling out” appendi-
citis during the initial triage assessment phase [14].
A meta-analysis of 29 studies by Ohle et al. [15] has shown that a
score of five (possible appendicitis) has a sensitivity of 99% and
specificity of 43%; scoring seven (probable appendicitis) decreases
sensitivity to 82% and increase specificity to 81%. This implies that
using a cutoff of five or less provides a good “ruling out score”, but a
cutoff point of seven or more cannot provide an adequate “ruling in
score”. Based on this, they suggest that patients with a score of
lower than five can be observed or serially examined, or discharged
 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162
Table 1
Alvadro scoring criteria for the diagnosis of appendicitis. A score of 5e6 is catego-
rized as possible appendicitis, a score of 7e8 categorized as probable appendicitis; a
score of more than 9 is considered very probable appendicitis.
Symptoms
Migratory Right Iliac Fossa Pain
Nausea/Vomiting
Anorexia
Signs
Rebound Tenderness In Right Iliac Fossa
Pyrexia (>37.3 " C)
Right Iliac Fossa Tenderness Laboratory Findings
Left Shift of neutrophils
Leucocytosis (>10,000)
Total Score
with follow-up safety netting instructions without the need for
radiological investigations [14].
Some smaller studies do call into question the accuracy of the
Alvarado score. McKay et al. [16] found that 5% of patients with an
Alvarado score of three or less had appendicitis, 36% of patients did
with a score between four and six. Gwynn et al. [1] found that only
8.4% with appendicitis had an Alvarado score below five. Another
study by Goldman et al. [17] found that 9% of cases with compli-
cated appendicitis would have been overlooked with use of the
Alvarado score.
Overall, as mentioned above the current evidence does support
the Alvarado score to be a reasonable starting point in the assess-
ment of suspected appendicitis. However, as per the evidence
mentioned above the Alvarado score cannot reliably predict
appendicitis without further investigations and therefore should
not be used alone in further management planning [28].
Another main critique of the Alvarado score is its applicability in
children and women of childbearing age [18]. In children, abdom-
inal pain is a common presentation in the absence of appendicitis
and the presentation of true appendicitis can be highly atypical. The
requirement for children to identify migration of pain, nausea and
anorexia can also be difficult. In women of childbearing age, gy-
necological conditions must be afforded equal consideration as
gastrointestinal causes of abdominal pain, and a diagnostic workup
will often involve other modalities very different to that of an
appendicitis workup.
Other assessment scores used in the diagnosis of appendicitis
include Eskelinen et al. [19], Fenyo et al. [20] and Lindeberg et al.
[21]. Ohman et al. [22] have reported that the Alvarado score out-
performs all these other scores.
In summary, the Alvarado scoring system most accurately pre-
dicts appendicitis in men and can be used as a reasonable starting
point in the assessment of suspected appendicitis cases. However,
as per the evidence mentioned above the Alvarado score cannot
reliably predict appendicitis without further investigations and
therefore should not be used alone in further management
planning.
2.2. Temperature
Pyrexial status is one of the predictive factors in the Alvarado
scoring system for appendicitis. However, many authors argue that
pyrexia is of limited predictive value when it comes to the diagnosis
of appendicitis. [23,24].
Andersson et al. [25] analysed the role of temperature in pre-
dicting appendicitis. They found that a temperature of more than
37.7 " C had a sensitivity of 70% and a specificity of 65%. Additionally,
they also calculated that a history of fever could predict
157
appendicitis with a likelihood ratio of 1.64. A high temperature has
also been reported as the third most common presenting symptom
in appendicitis [26] i.e. 94% presents with abdominal pain, 83% with
vomiting, 80% with a high temperature, 74% with refusal to eat and
Score 32% with diarrhea [25,27].
1 In support of the predictive value of pyrexia in appendicitis, a
1 meta-analysis [24] found that the average measured temperature
1
in a non-surgical abdomen is 37.7 " C (37.8 " C in appendicitis), with
1 it's persistence on serial examination significantly indicating the
1 presence of advanced appendicitis.
2 This mata-analysis reported the receiver operating character-
1
istic (ROC) curve for all appendicitis on initial examination to be
2
10
0.56, increasing to 0.77 on serial examination. What this signifies is
that, a smaller increase temperature value is needed in order to
predict pathology with the same level of accuracy [24].This sug-
gests that initial temperature may not have much predictive value,
but its use during subsequent measurements is warranted.
2.3. The role of laboratory markers
2.3.1. White Cell Count (WCC)
The role of white cell count (WCC) in the diagnosis of acute
appendicitis has been extensively studied. It is the most commonly
used investigation in the workup of suspected appendicitis. It's
increase in response to any inflammatory condition means, it is of
limited use in the differential diagnosing of appendicitis [28].
Shogilev et al. [29] looked at the sensitivity, specificity, likeli-
hood ratios and overall accuracy of WCC in the diagnosis of
appendicitis (Table 2). A WCC cut-off value of higher than
10,000e12,000 cell/mm3 yielded sensitivity values between 65%
and 85% and specificity values between 32% and 82%.
The studies used varied WCC cut-off points, with unclear con-
clusions on what cutoff point is best in the context of appendicitis
[30e33].The accuracy values of an elevated WCC expressed as an
area under the curve (AUC) is also shown in Table 2.
It is clear from Table 2 that WCC by itself is not adequate to
predict appendicitis [23,25,33e38].
Therefore should not be relied upon to change the diagnostic
workup or further management on its own. We can see from the
table that a WCC of >10,000 cells/mm3 starts to have a high diag-
nostic sensitivity but poor specificity, consistent with its non-
specific role in inflammatory responses.
2.4. C - Reactive Protein (CRP)
CRP is an acute phase reactant that begins to rise 8e12 h after
the onset of an inflammatory process, peaking between 24 and
48 h. This peak is later than that of WCC's (between 6 and 8 h). CRP
is widely considered a poor marker for early or uncomplicated
appendicitis, but a strong indicator for complicated or late-stage
appendicitis. [42] [43].
Shogilev et al. [29] (Table 3) analysed 12 studies (including two
meta-analyses) and concluded that a CRP cut-off level of >10 mg/L
yielded a range of sensitivities between 65 and 85% and specificities
between 59 and 73% [25,30,33,34,44,45].
Wu et al. [30] found that the accuracy in predicting appendicitis
(expressed as AUC) of CRP on day one of actual appendicitis was
0.60. This increased to 0.77 on day two and subsequently 0.88 on
day three.
In cases of complicated appendicitis, the accuracy (AUC) was
reported to be 0.90 on day one, 0.92 on day two and 0.96 on day
three [40]. This is consistent with the current knowledge that CRP
serves as a strong predictor for complicated or late-stage appen-
dicitis but is limited for its early diagnosis [40,46].
158 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162

Table 2
Operating characteristics for the white blood cell count as a predictor of appendicitis.

Study Cohort size WCC (10,000 cell/mm3) Sensitivity (%) Specificity (%) þLR -LR AUC (Accuracy) Study type

Agarwal et al. [32] 145 >11 79 55 1.76 0.38 e Prospective

Al-gaithy et al. [35] 456 >9.4 77 66 2.26 0.35 0.70 Retrospective
Anderson et al. [24] 502 >10 78 68 2.44 0.33 0.80 Observational
Anderson et al. [25] 3382 >10 83 67 2.52 0.26 e Meta-Analysis of 14 studies
>15 25 93 3.57 0.81
Deballon et al. [49] 135 >9.6 86 43 1.51 0.33 0.75 Prospective
Fergusson et al. [36] 1013 >12 74 72 2.64 0.36 0.80 Retrospective
Keskek et al. [39] 540 >10.5 84 53 1.79 0.30 e Retrospective
Khan et al. [40] 259 >11 83 62 2.18 0.27 e Retrospective
Kharbandaa et al. [37] 280 >14.6 68 80 3.4 0.4 0.78 Prospective
Mentes et al. [41] 201 >11.9 72 77 3.13 0.36 0.72 Retrospective
Ng et al. [48] 282 >11 82 39 1.34 0.46 e Retrospective
Sengupta et al. [44] 98 >11 65 72 2.32 0.49 e Prospective
Shaw et al.b [45] 297 e 70; 71 82; 55 3.9; 1.6 0.37; 0.53 e Retrospective cohort
Wu et al. [31] 144 >11 80 71 2.76 0.28 Retrospective
Xharra et al. [34] 173 >10 85 68 2.66 0.22 0.83 Prospective
Yang et al. [50] 897 10.4 86 32 1.26 0.44 Retrospective
Yidrim et al. [38] 85 >12.4 87 64 2.42 0.2 0.84 Retrospective
Yu et al. [59] 1011 Elevated (Pooled) 62 75 2.48 0.51 0.72 Meta-analysis of seven studies

WCC: white cell count.

LR: likelihood ratio.
AUC: area under the curve.
a
Paediatric study between ages 3e18 years.
b
Study was carried out on two different sites with two different results.

Table 3
Operating characteristics for C-reactive protein as a predictor of appendicitis.

Study Cohort size CRP (mg/L) Sensitivity (%) Specificity (%) þLR -LR AUR (Accuracy) Study Type

Andersson et al. [24] 481 >10 80 60 2 0.33 Observational

Andersson et al. [26] 1889 Appendicitis>10 81 59 1.98 0.32 0.75 Meta-analysis of 9 Studies
521 Perforated>10 91 79 4.33 0.11 0.87
Deballon et al. [49] 135 >6 91 74 3.5 0.12 0.85 Prospective
Khan et al. [40] 259 17 76 84 4.75 0.29 Retrospective
Ng et al. [48] 282 >8 68 36 1.06 0.89
Noh et al.a,[47] 307 >5 86 35 1.32 0.4 Retrospective
Sengupta et al. [44] 98 >10 65 68 2.03 0.51 Prospective
Shaw et al.b,[45] 297 >10 65; 68 73; 64 2.41; 1.89 0.48; 0.5 Retrospective
Wu et al. [43] 542 Appendicitis>15 38 81 2.00 0.77 0.60 Retrospective
Perfortated>10 77 89 7.12 0.26 0.90
Xharra et al. [34] 173 >10 85 72 3.04 0.21 0.83 Prospective
Yang et al. [50] 897 >8 77 26 0.88 Retrospective
Yu et al. [60] 1011 Elevated (pooled) 57 87 0.49 0.49 0.75 Meta-analysis of 5 studies

CRP: C-reactive protein.

LR: likelihood ratio.
AUR: area under the curve.
a
Hazard Ratio: 2.53 e Highest marker for complicated appendicitis.
b
Study performed at two different sites with different results.

2.5. Granulocyte count and Proportion of Polymorphonuclear
(PMN) cells
10 publications (Table 4) (one meta-analysis included) of gran-
ulocyte count and proportion of PMN assessed their sensitivities,
specificities, likelihood ratios and accuracies (measured as AUC) in
the diagnosis of acute appendicitis.
A modestly elevated PMN of greater than 7e7.5 # 109 cells/L
yielded a range of sensitivity of 71e89% and a specificity of 48e80%
in diagnosis of acute appendicitis [25,30,35,36,42].
Andersson et al. [30] shows a granulocyte count of more than
11 # 109/L has a greater likelihood ratio than any other laboratory
marker measured in the discriminatory diagnosis of appendicitis.
However, a clinically significant level requires the PMN to be
greater than 13 # 109 (cells/L). At this value, a study found that PMN
proportion can be valuable in the prediction of appendicitis with a
likelihood ratio of 7.09 and 6.67, respectively [36].
We can see from Table 4 that a PMN proportion of greater than
75% serves as a good discriminator of acute appendicitis but has
limited clinical value due to low specificities ranging between 33
and 84% [25,30,34,36,48e50]. Additionally, likelihood ratios are not
high enough to change the threshold of diagnosing appendicitis.
In the assessment of the “left shift” phenomenon, defined as a
band form count of >700/microliter; a retrospective study [36] of
1013 subjects found that it has a sensitivity of 28%, a specificity of
87%, an accuracy (AUC) of 0.58, and a likelihood ratio of 2.17 (Their
results were not clinically significant).
Another study of paediatric patients (mean age of 9.7 years)
showed that a “left shift” had a sensitivity of 59%, a specificity of
90%, and a likelihood ratio of 5.7 [51]. This suggests that while left
shift may provide diagnostic clues for appendicitis, it cannot
definitively diagnose appendicitis.
 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162 159

Table 4
Operational characteristics for Polymorphonuclear (PMN) count and ratio as a predictor of appendicitis.

Study Cohort size PMN Count (x109/L) Sensitivity (%) Specificity (%) LRþ LR- Accuracy (AUC) Study type

Al-gaithy et al. [35] 456 >7.5 71 66 2.09 0.44 0.68 Retrospective

Andersson et al. [24] 502 >11 48 92 6 0.57 0.80 Observational
Andersson et al. [26] 882 >7 85 48 1.64 0.31 0.77 Meta-analysis of three studies
>9 66 75 2.64 0.45
>13 29 96 7.09 0.74
Fergusson et al. [36] 1013 >7 89 59 2.17 0.19 0.83 Retrospective
>11 59 88 4.91 0.47
>13 40 94 6.67 0.64
Kharbanda et al. [37] 280 >11 69 75 2.76 0.41 0.78 Prospective
Shaw et al.a,[45] 297 >7.5 80; 74 80; 50 4; 1.5 0.25; 0.5 Retrospective
Study Cohort size PMN ratio (%) Sensitivity Specificity (%) LRþ LR- Accuracy (AUC) Study type
(%)
Andersson et al. [24] 502 >70 93 49 1.82 0.14 0.79 Observational
>85 52 88 4.33 0.55
Anderson et al. [26] 1494 >75 66 84 4.13 0.41 0.78 Meta-analysis of five studies
Deballon et al. [49] 134 >75 83 46 1.54 0.37 0.69 Prospective
Fergusson et al. [36] 1013 >70 87 61 2.23 0.21 0.78 Retrospective
>85 32 90 3.2 0.76
Ng et al. [48] 282 >80 60 77 2.61 0.52 Retrospective
Xharra et al. [34] 173 >75 79 68 2.47 0.31 0.78 Prospective
Yang et al. [50] 897 >74 87 33 1.3 0.39 Retrospective
a
Study performed at two different sites with different results.

2.6. The role of combined laboratory markers in the diagnosis of
appendicitis
In response to the need for a multifactor approach in the diag-
nosis of appendicitis, many small studies have shown encouraging
results due to the combining of predictive and discriminatory
powers of individual markers. However, many of these studies are
limited by secondary and post-hoc analyses, and further validation
of their conclusions is warranted [29].
An observational study by Andersson et al. [25] concluded that
the combined accuracy of clinical and laboratory markers, i.e.
temperature, WBC, CRP, PMN cells and PMN ratio has an accuracy
(AUC) of 0.85. This is greater than combining accuracies of all ele-
ments of the disease history (AUC 0.78). In comparison, the com-
bined accuracy of clinical findings is 0.87 (AUC). In another study
(49 cases with confirmed appendicitis out of 102 suspected cases),
the combined accuracy of: WCC>109 cells/L and CRP>6 mg/L was
0.96 (AUC). This had a likelihood ratio of 23.32 when all variables
were present. The accuracy was reported to be 0.53 (AUC) when at
least one variable was present and 0.03 (AUC) when none of the
variables were present [30].
Yang et al. [46] calculated a high sensitivity of 99% and low
specificity of 6% when either one of the inflammatory markers
(WBC % 10.4 # 103 cells/mm3, CRP % 8 mg/L, PMN Ratio >74%) was
present. They also report a high sensitivity of 98% and low speci-
ficity of 12% when one of either WCC or CRP was elevated. Other
studies also confirmed a high sensitivity value but a lower sensi-
tivity value [41,42]. The studies we reviewed used different cut-off
levels; therefore it was very difficult to compare them against each
other.
In summary, the evidence suggests acute appendicitis can be
ruled out when WBC, CRP and PMN ratio are all within normal
limits. An increase of a single blood marker should not be relied
upon to indicate appendicitis. A combination of positive markers
increases the likelihood of an accurate diagnosis of appendicitis,
but this still needs to be correlated clinically as they are all non-
specific markers of inflammation.
While these studies are further limited by secondary and post-
hoc analyses, they do prove there is a need for a multi-marker
approach. However, more research is needed to establish a new
methodology for use clinically.
2.7. Novel markers in the diagnosis of appendicitis
Table 5 summarises some of the most studied novel markers in
the diagnosis of acute appendicitis.
2.8. Interleukin 6 (IL-6)
IL-6 is a well-known cytokine that plays a central role in the
activation of the immediate inflammatory response. Kharbanda
et al. [37] found increased IL-6 levels during early stages of
appendicitis. They reported a sensitivity of 82% and a specificity of
69% at different cut-off points with accuracy (AUC) of 0.78. This
suggests a positive relationship between the degree of inflamma-
tion to the concentration of IL-6 [40,52]. Additionally, Paajanen
et al. [39] found the sensitivity (80%), specificity (84%) and accuracy
(AUC 0.80) of IL-6 in predicting appendicitis to be higher than
either that of WBC and CRP.
These studies confirm a relationship between IL-6 levels and the
early phase of appendicitis, but it has not been proven to be su-
perior to other blood markers in the diagnosis of appendicitis [29].
2.9. Serum Amyloid A (SAA)
This is a non-specific marker of inflammation and, in children it
has been shown to have a role in diagnosing appendicitis in early
stages. Lycopoulou et al. [53] calculated that SAA predicted
appendicitis with a sensitivity of 86% and a specificity of 83% with
an accuracy (AUC) of 0.96. They also argue that SAA has an early and
dynamic response to inflammatory conditions in general compared
to that of WBC and CRP. SAA can be useful in the early diagnosis of
appendicitis but further studies are needed to solidify this
argument.
2.10. Leukocyte gene expression (Riboleukograms)
These proteins have demonstrated potential for being a highly
sensitive marker for appendicitis (sensitivity 89%, specificity 66%)
[54]. However, major drawbacks in implementing such markers in
clinical practice include practically, the cost and real-time technical
feasibility [54].
160 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162
Table 5
Summary of results for different novel markers in diagnosing appendicitis.
Study Novel Marker Cohort size
Kharbanda et al. [37] Interleukin 6 280
Paajanen et al. [42] Interleukin 6 80
Lycopoulou et al. [53] Serum Amyloid A 42
Muenzer et al. [54] Riboleukograms 8 N/A
Kentsis et al. [57] Urine Leucine-rich a-2-glycoprotein 49
Bealer et al. [58] Calprotectin 181
Milla et al. [59] Calprotectin 843
AUC: area under the curve.
2.11. Granulocyte colony-stimulating factor
(G-CSF) acts on the bone marrow to stimulate production and
release of granulocytes into the peripheral blood. It is correlates
with the severity of an inflammatory response. It has been shown
to have the potential to aid other diagnostic measures while also
signifying the severity of acute appendicitis. Its use in the predic-
tion of acute appendicitis in children has been reported to have a
sensitivity of 91% and a specificity of 51% with accuracy (AUC) of
0.76 [55].
2.12. Urine Leucine-rich a-2-glycoprotein (LRG)
This marker has shown promise as a diagnostic marker for the
diagnosis of acute appendicitis in children. LRG has been found to
be elevated in patients with acute appendicitis in the absence of
macroscopic changes. It has also been hypothesized that LRG is
released earlier in the urine than locally recruited neutrophils. It
has also been shown to increase in pyelonephritis and other bac-
terial infections [29].
Studies [56,57], on urine LRG via a select ion-monitoring mass-
spectrometry assay has shown a high accuracy (AUC) of 0.99.
However, commercially available LRG-ELISAs only have accuracies
(AUC) of around 0.80 (secondary to an immunoassay interference
effect). This is still highly significant compared to many other novel
markers.
Current research efforts are focused on analyzing, whether
increased urine LRG is sufficiently sensitive and specific in aiding
the diagnosis of appendicitis. More research is needed to develop a
standardised and practical laboratory technique that is able to
accurately measure LRG in the clinical environment.
2.13. S100A8/A9 (Cal-protectin)
S100A8/A9 is a calcium-binding protein, which has been asso-
ciated with acute inflammation specific of the gastrointestinal tract.
Bealer et al. [58] were the first to study its use as a diagnostic tool in
acute appendicitis. In their study they reported a sensitivity of 93%,
a specificity of 54% and accuracy (AUC) of 0.75.
In a similar study by Mills et al. [59] the reported sensitivity was
96%, specificity was 16%, accuracy was (AUC) of 0.66. One of reasons
stated for this difference was how they measured the value of ELISA
for Calprotectin-a “shipping effect” where the test values were
inflated due to the delay in analysis that resulted in a 13%e43%
increase in its actual levels.
At this stage, Calprotectin has shown promise as a contributing
marker of appendicitis that will differentiate it from non-
gastrointestinal causes of abdominal pain [60]. However, due to
the low specificity, it is unlikely to be used as a diagnostic marker of
appendicitis in itself.
Cut-off Sensitivity (%) Specificity (%) Accuracy (AUC) Study Type
11.3 pg/mL 82 69 0.78 Prospective
14 pg/mL 84 79 0.80 Prospective
45 pg/mL 86 83 0.96 Prospective
80 66 e Prospective
3.9 mg/mL e e 0.99 Prospective
20 Elisa Units 93 54 0.71 Prospective
14 Elisa units 96 16 0.66 Prospective
2.14. Radiological imaging
CT is hailed as the gold standard in diagnosing appendicitis
(sensitivity and specificity reported between 83% and 98%). It has
shown to decrease negative appendectomy rates to less than 10%
(compared to 21.5% in the pre-CT era). On the other hand, literature
reports ultrasound scanning (USS) to be the most commonly used
imaging method in confirming the diagnosis of appendicitis
(sensitivity and specificity between 71% and 97%) [61].
Both these techniques have their own limitations, for USS
common problems include operator-dependent variability, and the
difficulty in visibility of the appendix due to body mass index,
anatomical variation and overlaying bowel gases. For CT, reporting
by the radiologist is a limiting factor, as well as considerations for
high exposure to ionizing radiation, contrast related complications
and relative high costs [62]. Efforts have been made to limit CT's
high radiation levels with low-dose CT imaging (which uses a
fourth of the standard dose of radiation).
Kim et al. [62] examined the use of this low-dose abdominal CT
for evaluating suspected appendicitis. In their single-center study
of 891 adolescents and young adults, they reported that low dose
CT and standard CT had similar negative appendectomy rates and
no major differences in perforation rates. Other smaller studies
have yielded similar results [63,64].
Evidence has suggested USS should be the preferred imaging
modality in children as well as pregnant and breast feeding women
[65e69]. To increase the sensitivity of diagnosis and to avoid the
radiation exposure of CT in equivocal cases, specific USS criteria and
repeated USS scans have been adopted. This has shown to improve
USS's diagnostic accuracy to up to 100% [70].
Some authors have recommended the use of CT in conjunction
with USS (USS-CT pathway). If clear signs of appendicitis are pre-
sent then surgery is performed without the need for a CT. Only in
equivocal cases are CT scans employed [71].
Poortman et al. [72] analysed 151 cases of suspected appendi-
citis, of these 79 patients had a positive USS, 71 patients had
confirmed appendicitis (verified during surgery). Those who had
inconclusive or a negative USS underwent CT scanning, of which 21
were positive for appendicitis (verified during surgery). This sig-
nifies initial USS is highly useful in detecting positive cases, and
further CT scanning for unequivocal cases can reliably pick up cases
that were falsely negative on USS. In another study (620 children,
USS equivocal) some received a follow-up CT while others were
observed. Here, there were no known missed diagnoses of appen-
dicitis [73].
Magnetic resonance imaging (MRI) is also used in young chil-
dren. Diagnostic imaging with USS selectively followed by radiation
free magnetic resonance imaging (MRI) protocol (similar to that of
USS-CT protocol) is possible. It has been shown to have no signifi-
cant differences in time to antibiotic administration, time to ap-
pendectomy, negative appendectomy rate, perforation rate or
length of stay in comparison with the USS-CT protocol [74].
 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162
In support of the above Aspelund et al. [75] has shown a high
USS-MRI pathway specificity (99%) with a sensitivity of 100%.
However the cost of MRI imaging remains the greatest deterrent in
adopting such a technique. Additionally, MRI scanning is time
consuming and may not be appropriate in the context of an acute
abdomen.
An optimal strategy combining US, CT and MRI is needed. A
balance needs to be made between reducing costs, low radiation
exposure, achieving a low negative appendectomy rate, and a fast
and correct diagnosis.
3. Conclusion
The purpose of this article is to present and summarise the latest
evidence regarding various approaches currently available in the
diagnostic workup of appendicitis. We included in our study dis-
cussions of clinical scoring systems, laboratory testing, radiological
imaging, and novel biomarkers for appendicitis.
In summary, in adults, raised Alvarado scores and laboratory
markers (WCC, CRP) all contribute to the suspicion of appendicitis.
When alone, none of them are able to predict the diagnosis in a
valid or reliable way. Subsequent surgical intervention should
therefore not be based on either of them alone.
However, when used in combination they show greater prom-
ise. A precise algorithm for the diagnosis of appendicitis based on a
combination of these variables will prove to be useful. We believe
also that many novel markers will be adopted and utilised suc-
cessfully in the future. Further research is warranted to determine
the effectiveness of these markers, and to continue searching for
undiscovered potential markers.
CT remains the best radiological modality for diagnosing
appendicitis but radiation exposure and long-term cancer risks are
a major concern. The use of USS-CT pathways or even USS-MRI
pathways increases diagnostic certainty without always having to
expose unclear cases to radiation. The alternative use of repeat USS
may reach a sensitivity of 100% [76].
The precise sequence and threshold for imaging pathways re-
mains are yet to be determined. In the meantime, we suggest
widespread consideration of using low-radiation CT that has
proven repeatedly to be just as sensitive as normal CT scanning or
repeated USS.
Ethical approval
Not Required.
Sources of funding
No Funding.
Author contribution
Mr S A Kabir (MBBS, MRCS, MMedSci medical education) study
design, data collections, data analysis, writing.
Mr S I Kabir (MBBS, MRCS, MSc) study design, data collections,
data analysis.
Dr R Sum (MBCH) data analysis.
Conflicts of interest
No conflicts of interest.
Research Registration Unique Identifying Number (UIN)
Review registry UIN 168.
161
Guarantor
Mr S A Kabir (MBBS, MRCS, MMedSci medical education) study
design, data collections, data analysis, writing.
References
[1] L.K. Gwynn, The diagnosis of acute appendicitis: clinical assessment versus
computed tomography evaluation, J. Emerg. Med. 21 (2) (2001) 119e123.
[2] F. Ferri, Appendicitis, acute, in: Mary Beth Murphy, et al. (Eds.), Ferri's Clinical
Advisor: Instant Diagnosis and Treatment, first ed., Mosby Elsevier, Philadel-
phia, 2009 (MD Consult. Elsevier, Inc).
[3] P. Ansari, Appendicitis. Merck Manual, Whitehouse Station, NJ. U.S.A, 2014.
[4] J.J. Hong, S.M. Cohn, A.P. Ekeh, et al., A prospective randomized study of
clinical assessment versus computed tomography for the diagnosis of acute
appendicitis, Surg. Infect. (Larchmt) 4 (2003) 231e239.
[5] K. Jones, A.A. Pena, E.L. Dunn, et al., Are negative appendectomies still
acceptable? Am. J. Surg. 188 (2004) 748e754.
[6] J.J. Naoum, W.J. Mileski, J.A. Daller, et al., The use of abdominal computed
tomography scan decreases the frequency of misdiagnosis in cases of sus-
pected acute appendicitis, Am. J. Surg. 184 (2002) 587e589.
[7] E. Bergeron, Clinical judgment remains of great value in the diagnosis of acute
appendicitis, Can. J. Surg. 49 (2) (2006) 96e100.
[8] D.R. Flum, A. Morris, T. Koepsell, et al., Has misdiagnosis of appendicitis
decreased over time? A population-based analysis, JAMA 286 (14) (2001)
1748e1753.
[9] T.W. Brown, M.L. McCarthy, G.D. Kelen, et al., An epidemiologic study of closed
emergency department malpractice claims in a national database of physician
malpractice insurers, Acad. Emerg. Med. 17 (5) (2010) 553e560.
[10] D.R. Flum, T. Koepsell, The clinical and economic correlates of misdiagnosed
appendicitis: nationwide analysis, Arch. Surg. 137 (2002) 799e804.
[11] B.J. Shea, C. Hamel, G.A. Wells, L.M. Bouter, E. Kristjansson, J. Grimshaw,
D.A. Henry, M. Boers, AMSTAR is a reliable and valid measurement tool to
assess the methodological quality of systematic reviews, J. Clin. Epidemiol. 62
(10) (2009 Oct) 1013e1020.
[12] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, The PRISMA Group, Preferred
reporting items for systematic reviews and meta-analyses: the PRISMA
statement, PLoS Med. 6 (7) (2009) e1000097.
[13] A. Alvarado, A practical score for the early diagnosis of acute appendicitis,
Ann. Emerg. Med. 15 (5) (1986) 557e564.
[14] B.W. Min, Change in the diagnosis of appendicitis by using a computed to-
mography scan and the necessity for a new scoring system to determine the
severity of the appendicitis, Ann. Coloproctol. 31 (5) (2015) 174e175, http://
dx.doi.org/10.3393/ac.2015.31.5.174.
[15] R. Ohle, F. O'Reilly, K.K. O'Brien, et al., The Alvarado score for predicting acute
appendicitis: a systematic review, BMC Med. 9 (2011) 139.
[16] R. McKay, J. Shepherd, The use of the clinical scoring system by Alvarado in
the decision to perform computed tomography for acute appendicitis in the
ED, Am. J. Emerg. Med. 25 (5) (2007) 489e493.
[17] R.D. Goldman, S. Carter, D. Stephens, et al., Prospective validation of the pe-
diatric appendicitis score, J. Pediatr. 153 (2) (2008), 278e28.
[18] H.E. Kim, S.B. Park, S.U. Woo, H.R. Rho, G.B. Chae, W.J. Choi, Application of the
Alvarado score to the diagnosis of acute appendicitis, J. Korean Soc. Colo-
proctol. 22 (2006) 229e234.
[19] M. Eskelinen, J. Ikonen, P. Lipponen, A computer-based diagnostic score to aid
in diagnosis of acute appendicitis: a prospective study of 1333 patients with
acute abdominal pain, Theor. Surg. 7 (1992) 86e90.
[20] G. Fenyo, Routine use of a scoring system for decision-making in suspected
acute appendicitis in adults, Acta Chir. Scand. 153 (1987) 545e551.
[21] G. Lindeberg, G. Feny, Algorithmic diagnosis of appendicitis using Bayes'
theorem and logistic regression, in: J.M. Bernardo, M.H. DeGroot, D.V. Lindley,
A.F. Smith (Eds.), Bayesian Statistics 3, Oxford University Press, Oxford, UK,
1988, pp. 665e669.
[22] C. Ohmann, Q. Yang, C. Franke, Diagnostic scores for acute appendicitis, Eur. J.
Surg. 161 (1995) 273e281.
[23] T. Cardall, J. Glasser, D.A. Guss, Clinical value of the total white blood cell count
and temperature in the evaluation of patients with suspected appendicitis,
Acad. Emerg. Med. 11 (10) (2004) 1021e1027.
[24] R.E. Andersson, A. Hugander, H. Ravn, et al., Repeated clinical and laboratory
examinations in patients with an equivocal diagnosis of appendicitis, World J.
Surg. 24 (4) (2000) 479e485.
[25] R.E. Andersson, A.P. Hugander, S.H. Ghazi, et al., Diagnostic value of disease
history, clinical presentation, and inflammatory parameters of appendicitis,
World J. Surg. 23 (2) (1999) 133e140.
[26] R.E. Andersson, Meta-analysis of the clinical and laboratory diagnosis of
appendicitis, Br. J. Surg. 91 (1) (2004) 28e37.
[27] K.L. Schwartz, E. Gilad, D. Sigalet, W. Yu, A.L. Wong, Neonatal acute appen-
dicitis: a proposed algorithm for timely diagnosis, J. Pediatr. Surg. 46 (2011)
2060e2064, http://dx.doi.org/10.1016/j.jpedsurg.2011.07.018. PMID:
22075333.
[28] J.D. Calder, H. Gajraj, Recent advances in the diagnosis and treatment of acute
appendicitis, Br. J. Hosp. Med. 54 (4) (1995) 129e133.
[29] Daniel J. Shogilev, Nicolaj Duus, Stephen R. Odom, Nathan I. Shapiro,
162 S.A. Kabir et al. / International Journal of Surgery 40 (2017) 155e162
Diagnosing appendicitis: evidence-based review of the diagnostic approach in
2014, West. J. Emerg. Med. 15 (7) (Nov. 2014) 859e871.
[30] R.E. Andersson, Meta-analysis of the clinical and laboratory diagnosis of
appendicitis, Br. J. Surg. 91 (1) (2004) 28e37.
[31] H.P. Wu, C.Y. Chen, I.T. Kuo, et al., Diagnostic values of a single serum
biomarker at different time points compared with Alvarado score and imaging
examinations in pediatric appendicitis, J. Surg. Res. 174 (2) (2012) 272e277.
[32] C.S. Agrawal, S. Adhikari, M. Kumar, Role of serum C-reactive protein and
leukocyte count in the diagnosis of acute appendicitis in Nepalese population,
NMCJ 10 (1) (2008) 11e15.
[33] C.W. Yu, L.I. Juan, M.H. Wu, C.J. Shen, J.Y. Wu, C.C. Lee, Systematic review and
meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein
and white blood cell count for suspected acute appendicitis, Br. J. Surg. 100
(2013) 322e329, http://dx.doi.org/10.1002/bjs.9008. PMID: 23203918.
[34] S. Xharra, L. Gashi-Luci, K. Xharra, et al., Correlation of serum C-reactive
protein, white blood count and neutrophil percentage with histopathology
findings in acute appendicitis, World J. Emerg. Surg. WJES 7 (1) (2012) 27.
[35] Z.K. Al-Gaithy, Clinical value of total white blood cells and neutrophil counts
in patients with suspected appendicitis: retrospective study, World J. Emerg.
Surg. WJES 7 (1) (2012) 32.
[36] J.A. Fergusson, K. Hitos, E. Simpson, Utility of white cell count and ultrasound
in the diagnosis of acute appendicitis, ANZ J. Surg. 72 (11) (2002) 781e785.
[37] A.B. Kharbanda, Y. Cosme, K. Liu, et al., Discriminative accuracy of novel and
traditional biomarkers in children with suspected appendicitis adjusted for
duration of abdominal pain, Acad. Emerg. Med. 18 (6) (2011) 567e574.
[38] O. Yildirim, C. Solak, B. Kocer, et al., The role of serum inflammatory markers
in acute appendicitis and their success in preventing negative laparotomy,
J. Invest. Surg. 19 (6) (2006) 345e352.
[39] M. Keskek, M. Tez, O. Yoldas, et al., Receiver operating characteristic analysis
of leukocyte counts in operations for suspected appendicitis, Am. J. Emerg.
Med. 26 (7) (2008) 769e772.
[40] M.N. Khan, E. Davie, K. Irshad, The role of white cell count and C-reactive
protein in the diagnosis of acute appendicitis, JAMC 16 (3) (2004) 17e19.
[41] O. Mentes, M. Eryilmaz, A. Hariak, et al., The value of serum fibrinogen level in
the diagnosis of acute appendicitis, Ulus. Travma Acil Cerrahi Derg. 18 (5)
(2012) 384e388.
[42] H. Paajanen, A. Mansikka, M. Laato, et al., Novel serum inflammatory markers
in acute appendicitis, Scand. J. Clin. Lab. Invest. 62 (8) (2002) 579e584.
[43] H.P. Wu, C.Y. Lin, C.F. Chang, et al., Predictive value of C-reactive protein at
different cutoff levels in acute appendicitis, Am. J. Emerg. Med. 23 (4) (2005)
449e453.
[44] A. Sengupta, G. Bax, S. Paterson-Brown, White cell count and C-reactive
protein measurement in patients with possible appendicitis, Ann. R. Coll. Surg.
Engl. 91 (2) (2009) 113e115.
[45] P.G. Vaughan-Shaw, J.R. Rees, E. Bell, et al., Normal inflammatory markers in
appendicitis: evidence from two independent cohort studies, JRSM Short. Rep.
2 (5) (2011) 43.
[46] M. Demircan, Plasma d-lactate level: a useful marker to distinguish a perfo-
rated appendix from acute simple appendicitis, J. Invest. Surg. 17 (3) (2004
May-Jun) 173e174 discussion 175.
[47] H. Noh, S.J. Chang, A. Han, The diagnostic values of preoperative laboratory
markers in children with complicated appendicitis, J. Korean Surg. Soc. 83 (4)
(2012) 237e241.
[48] K.C. Ng, S.W. Lai, Clinical analysis of the related factors in acute appendicitis,
Yale J. Biol. Med. 75 (1) (2002) 41e45.
[49] P. Ortega-Deballon, J.C. Ruiz de Adana-Belbel, A. Hernandez-Matias, et al.,
Usefulness of laboratory data in the management of right iliac fossa pain in
adults, Dis. Colon Rectum 51 (7) (2008) 1093e1099.
[50] H.R. Yang, Y.C. Wang, P.K. Chung, et al., Laboratory tests in patients with acute
appendicitis, ANZ J. Surg. 76 (1e2) (2006) 71e74.
[51] L.T. Wang, K.A. Prentiss, J.Z. Simon, et al., The use of white blood cell count and
left shift in the diagnosis of appendicitis in children, Pediatr. Emerg. Care 23
(2) (2007) 69e76.
[52] C.G. Murphy, J.N. Glickman, K. Tomczak, et al., Acute appendicitis is charac-
terized by a uniform and highly selective pattern of inflammatory gene
expression, Mucosal Immunol. 1 (4) (2008) 297e308.
[53] L. Lycopoulou, C. Mamoulakis, E. Hantzi, et al., Serum amyloid A protein levels
as a possible aid in the diagnosis of acute appendicitis in children, Clin. Chem.
Lab. Med. 43 (1) (2005) 49e53.
[54] J.T. Muenzer, D.M. Jaffe, S.J. Schwulst, et al., Evidence for a novel blood RNA
diagnostic for pediatric appendicitis: the riboleukogram, Pediatr. Emerg. Care
26 (5) (2010) 333e338.
[55] L. Allister, R. Bachur, J. Glickman, et al., Serum markers in acute appendicitis,
J. Surg. Res. 168 (1) (2011) 70e75.
[56] A. Kentsis, S. Ahmed, K. Kurek, et al., Detection and diagnostic value of urine
leucine-rich alpha-2-glycoprotein in children with suspected acute appendi-
citis, Ann. Emerg. Med. 60 (1) (2012), 78e83 e71.
[57] A. Kentsis, Y.Y. Lin, K. Kurek, et al., Discovery and validation of urine markers
of acute pediatric appendicitis using high-accuracy mass spectrometry, Ann.
Emerg. Med. 55 (1) (2010), 62e70 e64.
[58] J.F. Bealer, M. Colgin, S100A8/A9: a potential new diagnostic aid for acute
appendicitis, Acad. Emerg. Med. 17 (3) (2010) 333e336.
[59] A.M. Mills, D.S. Huckins, H. Kwok, et al., Diagnostic characteristics of S100A8/
A9 in a multicenter study of patients with acute right lower quadrant
abdominal pain, Acad. Emerg. Med. 19 (1) (2012) 48e55.
[60] C.W. Yu, L.I. Juan, M.H. Wu, C.J. Shen, J.Y. Wu, C.C. Lee, Systematic review and
meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein
and white blood cell count for suspected acute appendicitis, Br. J. Surg. 100
(2013) 322e329.
[61] M. Hernanz-Schulman, CT and US in the diagnosis of appendicitis: an argu-
ment for CT, Radiology 255 (2010) 3e7, http://dx.doi.org/10.1148/
radiol.09091211. PMID: 20308436.
[62] K. Kim, Y.H. Kim, S.Y. Kim, et al., Low-dose abdominal CT for evaluating sus-
pected appendicitis, N. Engl. J. Med. 366 (17) (2012) 1596e1605.
[63] C. Keyzer, D. Tack, V. de Maertelaer, et al., Acute appendicitis: comparison of
low-dose and standard-dose unenhanced multi- detector row CT, Radiology
232 (1) (2004) 164e172.
[64] H. Seo, K.H. Lee, H.J. Kim, et al., Diagnosis of acute appendicitis with sliding
slab ray-sum interpretation of low-dose unenhanced CT and standard-dose
i.v. contrast-enhanced CT scans, AJR Am. J. Roentgenol. 193 (1) (2009)
96e105.
[65] S. Gamanagatti, S. Vashisht, A. Kapoor, S. Chumber, S. Bal, Comparison of
graded compression ultrasonography and unenhanced spiral computed to-
mography in the diagnosis of acute appendicitis, Singap. Med. J. 48 (2007)
80e87.
[66] E.B. Wilson, J.C. Cole, M.L. Nipper, D.R. Cooney, R.W. Smith, Computed to-
mography and ultrasonography in the diag- nosis of appendicitis: when are
they indicated? Arch. Surg. 136 (2001) 670e675.
[67] P.M. Rao, G.W. Boland, Imaging of acute right lower abdomi- nal quadrant
pain, Clin. Radiol. 53 (1998) 639e649.
[68] P.J. Pickhardt, E.M. Lawrence, B.D. Pooler, et al., Diagnostic performance of
multidetector computed tomography for suspected acute appendicitis, Ann.
Intern Med. 154 (12) (2011), 789e796,W-291.
[69] A.S. Doria, R. Moineddin, C.J. Kellenberger, et al., US or CT for diagnosis of
appendicitis in children and Adults? A meta-analysis, Radiology 241 (1)
(2006) 83e94.
[70] A. Dilley, D. Wesson, M. Munden, J. Hicks, M. Brandt, P. Minifee, J. Nuchtern,
The impact of ultrasound examinations on the management of children with
suspected appendicitis: a 3-year analysis, J. Pediatr. Surg. 36 (2001) 303e308,
http://dx.doi.org/10.1053/jpsu.2001.20702. PMID: 11172421.
[71] R. Krishnamoorthi, N. Ramarajan, N.E. Wang, B. Newman, E. Rubesova,
C.M. Mueller, R.A. Barth, Effectiveness of a staged US and CT protocol for the
diagnosis of pediatric appendicitis: reducing radiation exposure in the age of
ALARA, Radiology 259 (2011) 231e239, http://dx.doi.org/10.1148/
radiol.10100984. PMID: 21324843.
[72] P. Poortman, H.J. Oostvogel, E. Bosma, et al., Improving diagnosis of acute
appendicitis: results of a diagnostic pathway with standard use of ultraso-
nography followed by selective use of CT, J. Am. Coll. Surg. 208 (3) (2009)
434e441.
[73] N. Ramarajan, R. Krishnamoorthi, L. Gharahbaghian, et al., Clinical correlation
needed: what do emergency physicians do after an equivocal ultrasound for
pediatric acute appendicitis? J. Clin. Ultrasound 42 (7) (2014) 385e394.
[74] L. Cobben, I. Groot, L. Kingma, E. Coerkamp, J. Puylaert, J. Blickman, A simple
MRI protocol in patients with clinically suspected appendicitis: results in 138
patients and effect on outcome of appendectomy, Eur. Radiol. 19 (2009)
1175e1183.
[75] G. Aspelund, A. Fingeret, E. Gross, D. Kessler, C. Keung, A. Thirumoorthi,
P.S. Oh, G. Behr, S. Chen, B. Lampl, W. Middlesworth, J. Kandel, C. Ruzal-
Shapiro, Ultrasonography/MRI versus CT for diagnosing appendicitis, Pediat-
rics 133 (2014) 586e593.
[76] A. Dilley, D. Wesson, M. Munden, J. Hicks, M. Brandt, P. Minifee, J. Nuchtern,
The impact of ultrasound examinations on the management of children with
suspected appendicitis: a 3-year analysis, J. Pediatr. Surg. 36 (2001) 303e308,
http://dx.doi.org/10.1053/jpsu.2001.20702. PMID: 11172421.