Accepted Manuscript

How to Diagnose an Acutely Inflamed Appendix; A Systematic Review of the Latest

Evidence

S.A. Kabir, S.I. Kabir, R. Sun, Sadaf Jafferbhoy, Ahmed Karim

PII: S1743-9191(17)30233-9
DOI: 10.1016/j.ijsu.2017.03.013
Reference: IJSU 3648

To appear in: International Journal of Surgery

Received Date: 1 December 2016

Revised Date: 11 February 2017
Accepted Date: 4 March 2017

Please cite this article as: Kabir S, Kabir S, Sun R, Jafferbhoy S, Karim A, How to Diagnose an Acutely
Inflamed Appendix; A Systematic Review of the Latest Evidence, International Journal of Surgery
(2017), doi: 10.1016/j.ijsu.2017.03.013.

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 ACCEPTED MANUSCRIPT
How to Diagnose an Acutely Inflamed Appendix; A Systematic Review of the Latest Evidence

SA. Kabir1, SI. Kabir2, R. Sun1, Sadaf Jafferbhoy1, Ahmed Karim1

1. Department of Surgery, Worcester Royal Hospital, UK

2. Department of Surgery, Oxford University Hospitals NHS trust, UK

Review registry UIN No: Review registry UIN 168

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Corresponding Author:
Dr Syed A Kabir
MBBS, MRCS, MMedSci Medical Education
Email: adnankabir58@hotmail.comContact No.: 00447907955889

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Address: 10 Ashton Court, Worcester, WR53FR ,UK

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 ACCEPTED MANUSCRIPT
How to Diagnose an Acutely Inflamed Appendix; A Systematic Review of the Latest Evidence

Abstract:

Acute appendicitis is the most common condition that presents with an acute abdomen needing
emergency surgery. 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.

The reported proportion of missed diagnoses of appendicitis ranges between 20% and 40%. A delay or
mis-diagnosis of appendicitis can result in severe complications such as perforation, abscess formation,
sepsis, and intra-abdominal adhesions.

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Literature has shown that patients who had a negative appendectomy 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 appendicitis is achieved to avoid
complications of both non-operating as well as unnecessary surgical intervention.

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The aim of this review is to systematically report and analyse the 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.

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Key words: Diagnosis of appendicitis; ALVARADO score; imaging and appendicitis; CT
and appendicitis; USS and appendicitis; laboratory markers in appendicitis; novel markers in
appendicitis

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How to Diagnose an Acutely Inflamed Appendix- A Systematic Review of the Latest Evidence
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Introduction
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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
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male to female ratio of three to two until the fourth decade of age.
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Despite this common presentation, correctly diagnosing appendicitis remains a challenge as clinical
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signs or positive blood results can be absent in 55% of the patients. The reported proportion of missed
diagnoses ranges between 20% and 40%; negative appendectomy rates are reported to range between
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4, 5, 6, 7, 8
10% and 34%.

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
9
hospital payoff in America.
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Flum et al showed that patients who had a negative appendectomy 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 appendicitis is achieved to avoid complications of both non-
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operating as well as unnecessary surgical intervention.

The aim of this review is to systematically report and analyse the latest evidence on the different
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approaches used in diagnosing appendicitis. We include discussions of clinical scoring systems,

laboratory tests, latest innovative bio-markers and radiological imaging.

Methods

This systematic review was carried out using the AMSTAR (Assessment of Multiple Systematic
11
Reviews) measurement tool. 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 combinations to generate the
maximum number of articles. The references of relevant articles were also screened and included if
relevant. Combination, truncation and explode functions were used.

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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.

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2. Inclusion of at least one of our outcome measures mentioned above.
3. Studies of only human subjects.
4. Publication language was English.

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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

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randomized controlled trials, meta-analyses, systematic reviews, retrospective studies, case series and
case reports.

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Fig. 1 PRISMA Flow Diagram.

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
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appendicitis in patients presenting with suspect abdominal pain. 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.
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Symptoms Score
Migratory Right Iliac Fossa Pain 1
Nausea / Vomiting 1
Anorexia 1

Signs
Rebound Tenderness In Right Iliac Fossa 1
Pyrexia (>37.3C ) 1
Right Iliac Fossa Tenderness 2

Laboratory Findings

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Left Shift of neutrophils 1
Leucocytosis (>10,000) 2

Total Score 10

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Table 1. Alvadro scoring criteria for the diagnosis of appendicitis. A score of 5-6 is categorized as possible
appendicitis, a score of 7-8 categorized as probable appendicitis; a score of more than 9 is considered very

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probable appendicitis.

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
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the use of the scoring system in ruling out appendicitis during the initial triage assessment phase.

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A meta-analysis of 29 studies by Ohle et al has shown that a score of five (possible appendicitis) has a
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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 with follow-up safety netting instructions without the need for radiological
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investigations .
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Some smaller studies do call into question the accuracy of the Alvarado score. McKay et al found that
5% of patients with an Alvarado score of three or less had appendicitis, 36% of patients did with a score
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between four and six. Gwynn et al found that only 8.4% with appendicitis had an Alvarado score below
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five. Another study by Goldman et al found that 9% of cases with complicated appendicitis would have
been overlooked with use of the Alvarado score.
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Overall, as mentioned above the current evidence does support the Alvarado score to be a reasonable
starting point in the assessment of suspected appendicitis. However, as per the evidence mentioned
above the Alvarado score cannot reliably predict appendicitis without further investigations and therefore
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should not be used alone in further management planning.
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Another main critique of the Alvarado score is its applicability in children and women of childbearing
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age. In children, abdominal 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
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of pain, nausea and anorexia can also be difficult. In women of childbearing age, gynecological
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.
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Other assessment scores used in the diagnosis of appendicitis include Eskelinen et al , Fenyo et al
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and Lindeberg et al .Ohman et al have reported that the Alvarado score out-performs all these other
scores.

In summary, the Alvarado scoring system most accurately predicts 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.

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
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appendicitis. ,

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25
Andersson et al analysed the role of temperature in predicting appendicitis. They found that a
temperature of more than 37.7C had a sensitivity o f 70% and a specificity of 65%. Additionally, they
also calculated that a history of fever could predict appendicitis with a likelihood ratio of 1.64. A high
26
temperature has also been reported as the third most common presenting symptom in appendicitis i.e.
94% presents with abdominal pain, 83% with vomiting, 80% with a high temperature, 74% with refusal
25, 27
to eat and 32% with diarrhea.
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In support of the predictive value of pyrexia in appendicitis, a meta-analysis found that the average
measured temperature in a non-surgical abdomen is 37.7C (37.8C in appendicitis), with its
persistence on serial examination significantly indicating the presence of advanced appendicitis.

This mata-analysis reported the receiver operating characteristic (ROC) curve for all appendicitis on

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initial examination to be 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
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accuracy. This suggests that initial temperature may not have much predictive value, but its use during
subsequent measurements is warranted.

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The role of laboratory markers

White Cell Count (WCC)

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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. Its increase in
response to any inflammatory condition means, it is of limited use in the differential diagnosing of
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appendicitis.

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Shogilev et al looked at the sensitivity, specificity, likelihood ratios and overall accuracy of WCC in the
diagnosis of appendicitis (Table 2). A WCC cut-off value of higher than 10,000-12,000 cell/mm3 yielded
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sensitivity values between 65% and 85% and specificity values between 32% and 82%.
The studies used varied WCC cut-off points, with unclear conclusions on what cutoff point is best in the
30, 31, 32, 33
context of appendicitis. The accuracy values of an elevated WCC expressed as an area under
the curve (AUC) is also shown in Table 2.
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23, 25, 33, 34, 35, 36, 37, 38

It is clear from table 2 that WCC by itself is not adequate to predict appendicitis.
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 diagnostic sensitivity
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but poor specificity, consistent with its non-specific role in inflammatory responses.
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Study Cohort WCC Sensitivity Specificity +LR -LR AUC Study type
size (10,000 (%) (%) (Accuracy)
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cell/mm

Agarwal et 145 >11 79 55 1.76 0.38 - Prospective

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Al-gaithy et 456 >9.4 77 66 2.26 0.35 0.70 Retrospective
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Anderson 502 >10 78 68 2.44 0.33 0.80 Observational
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et al
Anderson 3382 >10 83 67 2.52 0.26 - Meta-Analysis of
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et al 14 studies
>15 25 93 3.57 0.81

Deballon et 135 >9.6 86 43 1.51 0.33 0.75 Prospective

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Fergusson 1013 >12 74 72 2.64 0.36 0.80 Retrospective
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et al
Keskek et 540 >10.5 84 53 1.79 0.30 - Retrospective
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Khan et al 259 >11 83 62 2.18 0.27 - Retrospective

Kharbanda* 280 >14.6 68 80 3.4 0.4 0.78 Prospective

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et al
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Mentes et 201 >11.9 72 77 3.13 0.36 0.72 Retrospective
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Ng et al 282 >11 82 39 1.34 0.46 - Retrospective

Sengupta et 98 >11 65 72 2.32 0.49 - Prospective

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Shaw et 297 - 70;71 82;55 3.9;1.6 0.37;0.53 - Retrospective
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al** cohort

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Wu et al 144 >11 80 71 2.76 0.28 Retrospective

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Xharra et 173 >10 85 68 2.66 0.22 0.83 Prospective
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Yang et al 897 10.4 86 32 1.26 0.44 Retrospective

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Yidrim et 85 >12.4 87 64 2.42 0.2 0.84 Retrospective
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Yu et al 1011 Elevated 62 75 2.48 0.51 0.72 Meta-analysis of
(Pooled) seven studies

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Table 2. Operating characteristics for the white blood cell count as a predictor of appendicitis.
*Paediatric study between ages 3 to 18 years; **study was carried out on two different sites with two
different results. (WCC: white cell count; LR: likelihood ratio; AUC: area under the curve)

C - Reactive Protein (CRP)

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CRP is an acute phase reactant that begins to rise 8 -12 hours after the onset of an inflammatory
process, peaking between 24-48 hours. This peak is later than that of WCCs (between 6-8 hours). CRP
is widely considered a poor marker for early or uncomplicated appendicitis, but a strong indicator for
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complicated or late-stage appendicitis. ,
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Shogilev et al (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 65-85% and specificities between 59-
25, 30, 33, 34, 44, 45
73%.
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Wu et al 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.
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In cases of complicated appendicitis, the accuracy (AUC) was reported to be 0.90 on day one, 0.92 on
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day two and 0.96 on day three. This is consistent with the current knowledge that CRP serves as a
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strong predictor for complicated or late-stage appendicitis but is limited for its early diagnosis.
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Study Cohort CRP (mg/L) Sensitivity Specificity +LR -LR AUR Study Type
size (%) (%) (Accuracy)
Andersson 481 >10 80 60 2 0.33 Observational
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Andersson 1889 Appendicitis 81 59 1.98 0.32 0.75 Meta-analysis

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et al >10 of 9 Studies
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521 Perforated> 91 79 4.33 0.11 0.87

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Deballon et 135 >6 91 74 3.5 0.12 0.85 Prospective
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Khan et al 259 17 76 84 4.75 0.29 Retrospective
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Ng et al 282 >8 68 36 1.06 0.89
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Noh et al* 307 >5 86 35 1.32 0.4 Retrospective

Sengupta et 98 >10 65 68 2.03 0.51 Prospective

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Shaw et 297 >10 65;68 73;64 2.41; 0.48;0.5 Retrospective
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Wu et al 542 Appendicitis 38 81 2.00 0.77 0.60 Retrospective
>15
Perfortated 77 89 7.12 0.26 0.90
>10
Xharra et 173 >10 85 72 3.04 0.21 0.83 Prospective
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Yang et al 897 >8 77 26 0.88 Retrospective
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Yu et al 1011 Elevated 57 87 0.49 0.49 0.75 Meta-analysis
(pooled) of 5 studies
Table 3. Operating characteristics for C-reactive protein as a predictor of appendicitis.*Hazard Ratio: 2.53

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Highest marker for complicated appendicitis; **Study performed at two different sites with different results.
(CRP: C-reactive protein; LR: likelihood ratio; AUR: area under the curve)

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Granulocyte Count and Proportion of Polymorphonuclear (PMN) Cells

10 publications (Table 4) (one meta-analysis included) of granulocyte count and proportion of PMN

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assessed their sensitivities, specificities, likelihood ratios and accuracies (measured as AUC) in the
diagnosis of acute appendicitis.

A modestly elevated PMN of greater than 7-7.5 x109 cells/L yielded a range of sensitivity of 71-89% and
25, 30, 35, 36, 42
a specificity of 48-80% in diagnosis of acute appendicitis.

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Andersson et al shows a granulocyte count of more than 1110 /L has a greater likelihood ratio than
any other laboratory marker measured in the discriminatory diagnosis of appendicitis. However, a
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clinically significant level requires the PMN to be greater than 13 x 10 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
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and 6.67, respectively.

We can see from Table 4 that a PMN proportion of greater than 75% serves as a good discriminator of
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acute appendicitis but has limited clinical value due to low specificities ranging between 33 and 84%.
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Additionally, likelihood ratios are not high enough to change the threshold of diagnosing
appendicitis.
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In the assessment of the left shift phenomenon, defined as a band form count of >700/microliter; a
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retrospective study of 1013 subjects found that it has a sensitivity of 28%, a specificity of 87%, an
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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
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59%, a specificity of 90%, and a likelihood ratio of 5.7. This suggests that while left shift may provide
diagnostic clues for appendicitis, it cannot definitively diagnose appendicitis.
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Study Cohort PMN Sensitivity Specificity LR+ LR- Accuracy Study type
size Count (%) (%) (AUC)
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(x10 /L)
Al-gaithy et 456 >7.5 71 66 2.09 0.44 0.68 Retrospective
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Andersson et 502 >11 48 92 6 0.57 0.80 Observational

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Andersson et 882 >7 85 48 1.64 0.31 0.77 Meta-analysis

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>9 66 75 2.64 0.45

>13 29 96 7.09 0.74

Fergusson et 1013 >7 89 59 2.17 0.19 0.83 Retrospective
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>11 59 88 4.91 0.47

>13 40 94 6.67 0.64

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Kharbanda 280 >11 69 75 2.76 0.41 0.78 Prospective
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Shaw et al* 297 >7.5 80;74 80;50 4;1.5 0.25;0.5 Retrospective

Study Cohort PMN ratioSensitivity Specificity LR+ LR- Accuracy Study type
size (%) (%) (%) (AUC)

Andersson et 502 >70 93 49 1.82 0.14 0.79 Observational

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>85 52 88 4.33 0.55
Anderson et 1494 >75 66 84 4.13 0.41 0.78 Meta-analysis
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Deballon et 134 >75 83 46 1.54 0.37 0.69 Prospective

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Fergusson et 1013 >70 87 61 2.23 0.21 0.78 Retrospective
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>85 32 90 3.2 0.76

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Ng et al 282 >80 60 77 2.61 0.52 Retrospective
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Xharra et al 173 >75 79 68 2.47 0.31 0.78 Prospective

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Yang et al 897 >74 87 33 1.3 0.39 Retrospective

Table 4. Operational characteristics for Polymorphonuclear (PMN) count and ratio as a predictor of
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appendicitis. *Study performed at two different sites with different results.

The role of combined laboratory markers in the diagnosis of appendicitis

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In response to the need for a multifactor approach in the diagnosis 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,
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and further validation of their conclusions is warranted.

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An observational study by Andersson et al concluded that the combined accuracy of clinical and
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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 elements of the disease history (AUC 0.78). In
comparison, the combined 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
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accuracy was reported to be 0.53 (AUC) when at least one variable was present and 0.03 (AUC) when
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none of the variables were present.
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Yang et al calculated a high sensitivity of 99% and low specificity of 6% when either one of the
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inflammatory markers (WBC 10.4 x 103 cells/mm3, CRP 8 mg/L, PMN Ratio >74%) was present.
They also report a high sensitivity of 98% and low specificity of 12% when one of either WCC or CRP
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was elevated. Other studies also confirmed a high sensitivity value but a lower sensitivity value.
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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.

Novel Markers in the diagnosis of appendicitis

Table 5 summarises some of the most studied novel markers in the diagnosis of acute appendicitis.

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Study Novel Marker Cohort Cut-off Sensitivity Specificity Accuracy Study Type
size (%) (%) (AUC)
Kharbanda Interleukin 6 280 11.3 82 69 0.78 Prospective
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et al pg/mL
Paajanen Interleukin 6 80 14 84 79 0.80 Prospective
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et al pg/mL
Lycopoulou Serum Amyloid 42 45 86 83 0.96 Prospective
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et al A pg/mL
Muenzer et Riboleukograms 8 N/A 80 66 - Prospective
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Kentsis et Urine Leucine- 49 3.9ug/ - - 0.99 Prospective
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al rich -2- mL
glycoprotein
Bealer et Calprotectin 181 20 93 54 0.71 Prospective

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al Elisa
Units

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Milla et Calprotectin 843 14 96 16 0.66 Prospective
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units
Table 5. Summary of results for different novel markers in diagnosing appendicitis. (AUC: area under the
curve).

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Interleukin 6 (IL-6)

IL-6 is a well-known cytokine that plays a central role in the activation of the immediate inflammatory
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response. Kharbanda et al 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
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0.78. This suggests a positive relationship between the degree of inflammation to the concentration of
40,52 39
IL-6. Additionally, Paajanen et al 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.
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These studies confirm a relationship between IL-6 levels and the early phase of appendicitis, but it has
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not been proven to be superior to other blood markers in the diagnosis of appendicitis.
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Serum Amyloid A (SAA)

This is a non-specific marker of inflammation and, in children it has been shown to have a role in
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diagnosing appendicitis in early stages. Lycopoulou et al calculated that SAA predicted appendicitis
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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.
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Leukocyte gene expression (Riboleukograms)

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These proteins have demonstrated potential for being a highly sensitive marker for appendicitis
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(sensitivity 89%, specificity 66%). However, major drawbacks in implementing such markers in clinical
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practice include practically, the cost and real-time technical feasibility.

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 prediction of acute appendicitis in children has been reported to have a
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sensitivity of 91% and a specificity of 51% with accuracy (AUC) of 0.76.

Urine Leucine-rich -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
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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 bacterial
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infections.
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Studies , 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.

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S100A8/A9 (Cal-protectin)

S100A8/A9 is a calcium-binding protein, which has been associated with acute inflammation specific of
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the gastrointestinal tract. Bealer et al were the first to study its use as a diagnostic tool in acute

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appendicitis. In their study they reported a sensitivity of 93%, a specificity of 54% and accuracy (AUC) of
0.75.
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In a similar study by Mills et al 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

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Calprotectin- a shipping effect where the test values were inflated due to the delay in analysis that
resulted in a 13%-43% increase in its actual levels.

At this stage, Calprotectin has shown promise as a contributing marker of appendicitis that will
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differentiate it from non-gastrointestinal causes of abdominal pain. However, due to the low specificity,

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it is unlikely to be used as a diagnostic marker of appendicitis in itself.
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Radiological Imaging

CT is hailed as the gold standard in diagnosing appendicitis (sensitivity and specificity reported between
83%-98%). It has shown to decrease negative appendectomy rates to less than 10% (compared to
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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
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specificity between 71%-97%).
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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
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considerations for high exposure to ionizing radiation, contrast related complications and relative high
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costs. Efforts have been made to limit CTs high radiation levels with low-dose CT imaging (which
uses a fourth of the standard dose of radiation).
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Kim et al examined the use of this low-dose abdominal CT for evaluating suspected appendicitis. In
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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.
63 64
Other smaller studies have yielded similar results. ,

Evidence has suggested USS should be the preferred imaging modality in children as well as pregnant
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65 66 67 68 69
and breast feeding women. , , , , 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.
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This has shown to improve USSs diagnostic accuracy to up to 100%.

Some authors have recommended the use of CT in conjunction with USS (USS-CT pathway). If clear
signs of appendicitis are present then surgery is performed without the need for a CT. Only in equivocal
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cases are CT scans employed.
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Poortman et al analysed 151 cases of suspected appendicitis, 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 signifies 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
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were no known missed diagnoses of appendicitis.

Magnetic resonance imaging (MRI) is also used in young children. Diagnostic imaging with USS
selectively followed by radiation free magnetic resonance imaging (MRI) protocol (similar to that of USS-

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 ACCEPTED MANUSCRIPT
CT protocol) is possible. It has been shown to have no significant differences in time to antibiotic
administration, time to appendectomy, negative appendectomy rate, perforation rate or length of stay in
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comparison with the USS-CT protocol.
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In support of the above Aspelund et al 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

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CONCLUSION

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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
discussions of clinical scoring systems, laboratory testing, radiological imaging, and novel biomarkers
for appendicitis.

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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 promise. A precise algorithm for the diagnosis of

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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 successfully in the future. Further research is
warranted to determine the effectiveness of these markers, and to continue searching for undiscovered
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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
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increases diagnostic certainty without always having to expose unclear cases to radiation. The
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alternative use of repeat USS may reach a sensitivity of 100%.

The precise sequence and threshold for imaging pathways remains are yet to be determined. In the
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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.
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 ACCEPTED MANUSCRIPT
Highlights

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

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Mr S A Kabir (MBBS, MRCS, MMedSci medical education) study design, data

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Dr R Sum (MBCH) data analysis

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PRISMA Flow Diagram:

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Fig. 1 PRISMA Flow Diagram.
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Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097
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