Abdominal pain is a common presenting complaint in the paediatric emergency department with appendicitis being the most common reason for abdominal surgery in the paediatric population . Traditionally a clinical diagnosis, the role of laboratory investigations and imaging vary with clinical context and continue to evolve as new technologies develop. The search continues for laboratory investigations which show better diagnostic utility than the commonly requested full blood count and C-reactive protein. The accuracy of computed tomography (CT) is countered by concern regarding the effects of radiation exposure leading to the testing of imaging algorithms utilizing ultrasound and MRI. Widely used clinical scoring systems remain inferior to experienced clinical judgement. Diagnostic algorithms are required that exploit the properties of the more powerful diagnostic tests available within a particular clinical context, while minimizing radiation exposure.
BIOMARKERS: THE USUAL SUSPECTS
An analysis of almost 1200 children admitted with a suspected diagnosis of appendicitis found that cases of complicated appendicitis were associated with higher white blood cell counts, a predominant neutrophilia and an abnormally raised C reactive protein (CRP) . Amongst those children less than 5 years of age, however, there was no statistically significant difference in CRP between those with a normal appendix or simple appendicitis on laparoscopy. Only when coupled with the physical exam does the test become useful .
Although the white cell count with neutrophil predominance is associated with appendicitis  the mean platelet volume (MPV) has also been suggested to be of value . As inflammation occurs there is an increase in platelet production and thus there is an increase in immature cell types in the serum. The mixed results from a variety of observational studies have not borne this out, revealing both raised and lowered MPV in the setting of appendicitis . It has also been found to be raised in other gastrointestinal disease states such as inflammatory bowel disease . This renders the test of little confirmatory value.
THE UNUSUAL SUSPECTS
Another biomarker that showed early promise is bilirubin. This haemoglobin breakdown product is probably raised as a result of bacterial endotoxins causing impaired bilirubin excretion . A pooled meta-analysis showed it to be of little benefit in predicting early appendicitis though is often raised in the case of acute perforation .
A number of unique inflammatory biomarkers are being considered as an adjunct to more traditional markers of inflammation. As molecular assays become more readily available researchers have been looking at specific metabolites of the inflammatory cascade to help determine the likelihood that a child has appendicitis. One combined cytokine/metabolic profile has been shown to be both highly sensitive (81%) and specific (100%) though the number of participants was small . Other potential assays such as myeloid-related protein 8/14 , neutrophil gelatinase-associated lipocalin  and calprotectin  have been linked with appendicitis.
These novel biomarkers have been tested in small numbers. It more likely that a combined panel, rather than a single blood test will help swing the needle of probability towards a diagnosis of acute appendicitis. Moving beyond inflammatory metabolomics, investigators have looked at RNA genomic sequencing for potential markers of appendicitis. This technology is not yet readily available or affordable but does show potential for future use.
An alternative approach is to look in the urine for a biomarker, such as leucine rich alpha-2-glycoprotein, that might indicate that a child is more likely to have appendicitis . As with the majority of serum tests, it is not specific enough to delineate the potential cause of paediatric abdominal pain.
Any potential biomarker needs to be accurate, easily obtainable, with results available in a timely fashion and it must not be cost-prohibitive. The search for an optimal candidate has not yet been satisfied.
Over the last 30 years, a number of scoring systems have been utilized in the diagnosis of appendicitis [14–16]. Each scoring system has sought to rapidly achieve the highest possible diagnostic certainty with the lowest clinical cost (blood tests, secondary radiation, unnecessary delays) to the patient.
Alvarado's seminal 1986 scoring system has been validated multiple times; a 2011 meta-analysis of the score's diagnostic accuracy identified 42 studies [17,18]. It utilizes Bayesian principles with a number of key indicators. These include signs [right lower quadrant (RLQ) tenderness, fever, rebound tenderness], symptoms (anorexia, migration of pain to RLQ, nausea or vomiting) and laboratory values (leukocytosis, left shift), with a view to reducing the ‘negative appendicectomy’ rate.
Samuel's 2002 enhancement of the Alvarado score, the Paediatric Appendicitis Score (PAS), further refined these criteria to be more applicable to a paediatric population, aged 4–15 years . Importantly, in their derivation studies, both PAS and Alvarado were evaluated as ‘rule in’ tests, hence they should not be used in an attempt to exclude appendicitis, a common misconception amongst clinicians.
The weaknesses of existing scoring systems are two-fold; first, they are reliant on a number of investigations, secondly (and more significantly) they should be robust at the extremes of presentation. This phenomenon is echoed in a number of complex scoring systems in other domains. They are let down by a large number of patients falling within the inconclusive cohort of patients who require increased diagnostic certainty.
More recently, Shah et al. sought to reduce CT use in diagnosis. This prospective study of 840 patients aimed to both accurately diagnose acute appendicitis and to reduce CT use through the use of an algorithm which prioritized ultrasound over both blood tests, as well as encouraging timely review by a surgeon. The ultrasound-based algorithm reported moderate success in reducing the equivocal group from 43 to 11%, with preserved ‘miss rate’ and a sensitivity of 69.2% and specificity of 94.0% for ultrasound scan (USS) in patients with suspected appendicitis.
There are several scoring systems targeting the diagnosis of acute appendicitis, including Raja Isteri Pengiran Anak Saleha Appendicitis, PAS, Alvarado and Shah. Although each provide a helpful diagnostic framework, none have been shown to be superior to the judgement of an experienced clinician.
Approaches to diagnostic imaging in RLQ pain vary with geography [20,21]. The US trend is a move away from CT scanning while attempting to maintain diagnostic accuracy. Much of the rest of the world is moving to decrease the rates of negative appendectomy while maintaining low rates of both missed appendicitis and radiation exposure.
Twenty-nine years after the first description of the use of ultrasound in the diagnosis of appendicitis , the American College of Radiology issued appropriateness criteria for imaging in RLQ pain recommending ultrasound as the first line option in children . Ultrasound use in the investigation of paediatric RLQ pain then increased, in a United States-based cohort, from 25% in 2005 to 61% in 2014 [24▪]. Increased awareness of the risks posed by radiation exposure in young people has led to a decrease in CT use from 62.6 to 32.7% over the same period [24▪].
Reduction of radiation exposure of children and young people from CT scanning is specifically listed as a national priority by the Australian Commission on Safety and Quality in Healthcare  adding administrative as well as clinical momentum to the move away from CT scanning in suspected appendicitis.
The clinical and major medico-legal risk surrounding appendicitis lies in missing the diagnosis leading to a mantra of ‘if in doubt, take it out’. The complication rates associated with appendectomy are becoming more apparent, even in the absence of appendicitis and as such this principle is receiving closer scrutiny with negative appendectomy rate gaining importance as a quality marker. In a US population of 250 783 children a negative appendectomy rate of 6.7% was achieved , comparing favourably with over 20% in one UK cohort .
The ability of nonradiologists to perform diagnostically useful point of care ultrasound scans (POCUS) after a relatively brief training period has been demonstrated repeatedly in several specialty groups including surgeons  and emergency physicians . These studies tend to focus on the sonographers ability to rule appendicitis in or out. The opportunity cost of potentially missed alternative diagnoses which may have been identified had the scan been done by a suitably qualified radiologist or radiographer has been poorly quantified to date. A large meta-analysis incorporating data from 21 studies and 8605 patients described POCUS as having a positive likelihood ratio of 9.24% and a negative likelihood ratio of 0.17 [30▪▪]. Likelihood ratios of this size represent diagnostically useful changes between pretest and postprobabilities of appendicitis and, indeed, are larger than those provided by several of the more commonly used tests including white cell count and CRP. Other studies have evaluated algorithms combining various clinical and biochemical markers with POCUS. These have been previously well described . The framing as a risk modifier rather than a rule in or rule out test is a more conceptually useful way to consider POCUS and its role in rationalizing the need for further imaging.
Secondary signs of appendicitis, which may be seen on POCUS, including loss of mural stratification, periappendiceal fat inflammation and the presence of an appendicolith are significant predictors of appendicitis in children with otherwise equivocal exams . The use of standardized reporting templates improved the reporting of these signs from 5.4 to 79.5% with an associated decrease in CT use in a single institution study . Some debate continues as to the upper limit of the normal appendiceal diameter, traditionally defined as 6 mm. A single institution retrospective chart review of 320 patients found a sensitivity of 100% and a specificity of 43% when 6 mm was used as the cut off of normal. This compared with a sensitivity of 94% and specificity of 71% when 7 mm was used instead . Bladder filling prior to USS made no difference to the diagnostic utility and this could be avoided in patients for whom ovarian abnormality is not a diagnostic concern .
CT dose reduction is also under scrutiny. A systematic review of 14 articles including 3262 adult and paediatric patients found no significant differences in sensitivity or specificity between scans utilizing up to 8 mSv and those where the dose was kept below 2 mSv , effectively showing an average of a 78% reduction in radiation dose did not affect the diagnostic utility of the test. This finding was re-enforced by a multicentre randomized controlled trial in 3074 adolescents and young adults across 20 sites which found limiting radiation dose to 2 mSv provided noninferior scans to those utilizing up to 8 mSv .
One algorithm utilizing USS with MRI for equivocal cases when evaluated over 1982 cases returned a sensitivity of 98.3% and a specificity of 97.1% [38▪] leading to a negative appendectomy rate of 0.2% . This study was performed in a tertiary children's hospital with USS yielding a higher than typical diagnostic accuracy. Though this may present a threat to the external validity of this dataset it does demonstrate that a highly accurate diagnostic algorithm avoiding the use of radiation is possible.
A surgical operation to remove the appendix has been the gold standard treatment for acute appendicitis for over 100 years, and predates the introduction of antibiotics . Although the operation is relatively straightforward, it does bring inherent risks to the patient, and over the last few years there has been much discussion about the alternative conservative treatment option (managing the patients with antibiotics only).
In children, in particular, families and surgeons may be keen to consider conservative options. Surgery requires a general anaesthetic and this carries inherent risks, along with the operation itself which is associated with a complication rate of up to 7% . Surgery also has emotional and psychological implications for families and children that can have a lasting impact. Whilst not having surgery would remove this risk, the alternative conservative approach has to be reliable in curing the appendicitis, and in ensuring there is an acceptably low rate of future recurrence of appendicitis.
Research into conservative management has moved from adult patients to paediatric patients. In 2017, two systematic reviews [42,43▪▪] analysed the evidence. Georgiou et al. included 10 studies and Kessler et al. included five (four of which were included in the Georgiou et al. article). The quality of the trials was found to be low with only one randomized controlled trial . Antibiotic regimens varied (including piperacillin-tazobactam, coamoxiclav, metronidazole and ciprofloxacin) and the length of treatment ranged from 3 to 10 days. Intravenous antibiotics were used for at least 24 h and patients were then changed to oral antibiotics. Georgiou et al. found that initial treatment was successful in 97% in the conservative group, but the recurrence rate of appendicitis was 14%. The complication rates were similar between the two groups. Kessler et al. found that there was a seven times increased risk of readmission for patient who had undergone conservative management.
Both reviews struggle to draw conclusions due to the heterogeneity of the studies and particularly as they included mainly nonrandomized studies. Both systematic reviews conclude that there is no significant benefit in choosing conservative management over surgical intervention. Further studies evaluating the role of nonoperative management in paediatric appendicitis are ongoing .
Acute abdominal pain is a common paediatric presentation, with appendicitis the most common surgical cause. There is a balance of risk between missing the diagnosis and harming the patient through unnecessary testing or surgery. A universally effective diagnostic algorithm remains elusive but an understanding of the risk stratification properties of each clinical, pathological and radiological test available is key in enabling clinicians to make decisions that are appropriate for their patient within their particular clinical context.
Financial support and sponsorship
Conflicts of interest
B.L. has received travel expenses from Advanced Paediatric Life Support Australia (APLS) and the Paediatric Research in Emergency Departments International Collaborative (PREDICT). All authors have received travel expenses from Paediatric Learning Xperience PTY.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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