Best evidence topic: Can acute appendicitis manifest with normal inflammatory markers?

A best evidence topic has been constructed using a described protocol. The three-part question addressed was: for patients with suspected acute appendicitis can normal inflammatory markers rule out the diagnosis? Altogether 151 papers were found using the search strategy reported below. Seven were identified to provide the best evidence to answer the question. The author, journal, date, and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses were tabulated. In conclusion, six out of seven papers are more in favour with the concept that normal inflammatory markers cannot effectively rule out the diagnosis of acute appendicitis.


Introduction
This Best Evidence Topic (BET) was devised using a framework outlined by the International Journal of Surgery [1]. This format was used because a preliminary literature search showed that the available evidence has insufficient quality and is too homogenous to conduct a meaningful meta-analysis. A BET provides evidence based answers to common clinical questions, using a systematic approach to reviewing the literature.

Clinical scenario
A 25-year-old female presents with a history of shifting right iliac fossa pain for two days, she has normal inflammatory markers and a negative pregnancy test. An abdominal ultrasound was not conclusive for appendicitis. You question whether normal inflammatory markers can rule out appendicitis and safely discharge the patient. The results were limited to English articles and human studies.

Search outcome
A total of 151 papers were found using OVID and PubMed interface. A total of 53 papers were identified after we removed duplicates. Out of these, 43 papers were excluded based on titles and abstracts. Ten fulltext articles were screened and assessed for eligibility. From these, seven papers were identified that provided the best evidence to answer the question. The search strategy process is detailed in Fig. 1. Eligible patients were defined as those presenting with both normal WCC and CRP with a histologically confirmed acute appendicitis. In addition to the false-negative result of these inflammatory markers, most of the included papers also investigated the sensitivity, specificity, positive and negative predictive values. However, we have mainly focused on the false-negative result because the rest is out of the scope of this best evidence topic.

Discussion
Shefki Xharra et al. [2] conducted a prospective double-blinded clinical study in 2012 to assess the accuracy of IM in the diagnosis of acute appendicitis: the false-negative result of both CRP and WCC was 6%. The conclusion was that the combination of CRP and WCC has greater diagnostic accuracy in acute appendicitis. This significantly  decreases false positive and false negative diagnoses, but none of these is 100% diagnostic for acute appendicitis. In 2015, Jasper J. Atema et al. [3] conducted a large multicentre retrospective review of five cohort studies of 1024 adult patients with clinically suspected AA who presented with a duration of symptoms ranging from 2 h to 5 days were included. They found 12 patients (11.8%) among those with normal IM had a final diagnosis of appendicitis. The conclusion was: no WCC count or CRP level can safely and sufficiently confirm or exclude the suspected diagnosis of acute appendicitis in patients who present with abdominal pain of 5 days or less in duration. Jason J. Y. Kim et al. [4] recently published a multicentre prospective observational study in 2019 to evaluate the relationship between normal IM, duration of symptoms, and proven appendicitis. Of interest was the finding that a total of 38.9 of patients with normal CRP and WCC had appendicitis. Therefore, the study concluded that normal inflammatory markers can't exclude appendicitis, even in those with prolonged duration of symptoms. PG Vaughan-Shaw et al. [5] in 2016 also reached the same conclusion after they conducted a retrospective two independent cohort studies to assess the relationship between normal IM and AA, they added neutrophils count in addition to WCC and CRP, they reported AA with normal inflammatory markers in 6.3% of the patients. They disagree with the view of Sengupta et al. [8]. Who suggests that patients with normal WCC and CRP are unlikely to have AA. Nalin H. Dayawansa et al. [6] reported an 8.54% rate of acute appendicitis with normal IM in their Case-control retrospective analysis which included 400 adult patients. Also, in 2001 JM Grönroos [7] conducted what was seems to be a case-control study which included 200 paediatric patients with suspected acute appendicitis and reported a 7% incidence of normal WCC and CRP among patients with AA.
In contrast to all of the above-mentioned studies which showed increasing evidence that normal IM markers are not effectively helpful to exclude AA, there is one study conducted by Anshuman Sengupta et al. [8]

Clinical bottom-line
Out of these seven studies, six have supported the concept that normal inflammatory marker levels cannot "rule out" acute appendicitis. Furthermore, the authors recommend relying on a combination of clinical signs, images and serial measurements of inflammatory markers to exclude a diagnosis of acute appendicitis.

Provenance and peer review
Not commissioned, externally peer reviewed.

Author contribution
Pushpa Veeralakshmanan: assisted in the data collection, analysis and writing of the paper. James Ackah and Pedram Panahi: assisted in writing of the paper.

Declaration of competing interest
There are no conflicts of interest.