Introduction
Acute appendicitis (AA) is one of the most common surgical emergencies, with a lifetime
risk of 7 % in the United states [1]. AA usually occurs secondary to obstruction of the appendiceal orifice. The obstruction
itself is most commonly caused by a piece of impacted stool called a fecalith. However,
obstruction of the appendix may also have other causes, such as tumors, infections,
or lymphoid hyperplasia [2]. This obstruction leads to distension of the appendix and manifests with clinical
symptoms of generalized abdominal pain, right lower quadrant pain, fever, nausea,
and vomiting. Further distension leads to arteriolar thrombosis, which results in
ischemia, gangrene and perforation [3].
The current standard of treatment for AA is laparoscopic appendectomy [4]. New data suggest that antibiotics instead of surgery could also be used for treatment
of appendicitis, and they were found to be non-inferior to laparoscopic surgery [5]
[6]. However, these studies showed that nearly 30 % of patients treated with antibiotics
had a repeat episode of appendicitis within 1 year [7]. Negative appendectomy rates (defined as appendectomy performed on a pathologically
normal appendix) range from 10 % to 15 %, leading to an increase in hospital costs
and morbidity [8]
[9]. The appendix is also now thought to play a role in immune function and to possibly
maintain the colonic flora, favoring the potential benefit of avoiding an appendectomy
[10]
[11].
Endoscopic retrograde appendicitis therapy (ERAT) is an endoscopic procedure used
for management of AA and is an alternative to laparoscopic appendectomy. This procedure
was first reported by Liu et al in 2012 [12]. The procedure consists of passage of a colonoscope to the opening of the appendix
for placement of a stent or drain in the infected appendix via the appendiceal orifice,
relieving appendiceal obstruction. The benefits of performing ERAT over laparoscopic
appendectomy are avoidance of surgical intervention, preservation of the appendix,
as well as direct visualization of the colon, with subsequent or concurrent management
of any abnormalities noted and possibly decreasing rates of negative appendectomy.
We present the first systematic review and meta-analysis to evaluate rates of success
and adverse events (AEs) with ERAT in management of AA.
Methods
Search strategy
Multiple databases such as PubMed, EMBASE, CINAHL, Cochrane and Google Scholar (from
inception to Jan 2022) were searched utilizing combinations of keywords such as: ‘endoscopic’,
‘retrograde’, ‘appendicitis’, ‘appendiceal’, ‘therapy’, ‘treatment’, ‘endoscopy’,
‘endoscope’ and ‘acute’. Reference lists from articles, conference proceedings and
prior reviews were also searched for additional articles. Two investigators (BD and
AP) independently carried out the search with discrepancies being resolved with assistance
from a third investigator (YN). This search was performed in accordance with preferred
reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. [13] This study selection is outlined in Supplementary Fig. 1 and PRISMA checklist is outlined in Supplementary Fig. 2.
Study selection
All studies evaluating the technical success, clinical success and AEs of ERAT in
AA irrespective of age were included in our final analysis. The following exclusion
criteria were used: (1) sample size < 10 patients; and (2) studies not in English
language. This study was not registered. In case of cohort overlap, the most comprehensive
study was included after discussion with three authors (BD, AP, YN).
Data abstraction and quality assessment
Two authors (BD and YN) independently reviewed each study for quality assessment using
the Newcastle-Ottawa scale (NOS) for cohort studies and Cochrane risk-of-bias tool
for randomized control trials (RCTs) [14]
[15]. Details of these scales are provided in Supplementary Table 1 and Supplementary Fig. 3.
Outcomes assessed
The primary outcomes assessed were technical and clinical success of ERAT in AA.The
secondary outcomes assessed were overall rates of AEs and AE subtypes.
Definitions
Technical success was defined as successful intubation of the appendix and successful
drainage of the appendiceal cavity with or without placement of a stent [10]
[11]
[16]
[17]
[18]
[19]. Clinical success was defined as improvement in symptoms such as abdominal pain,
nausea, and fever [10]
[11]
[17]
[18]
[19]
[20]. AEs were related directly to the procedure, such as bleeding and perforation.
Statistical analysis
A random effects model was used to calculate pooled estimates for each outcome of
interest as suggested by the meta-analysis techniques by DerSimonian and Laird [21]. Forest plots were used for presentation of our results. A continuity correction
of 0.5 would be added prior to statistical analysis if zeros occurred in incidence
of an outcome of a study [22]. We utilized the Cochran Q statistical test and I2statistics to assess heterogeneity [23]
[24]. Low, moderate, substantial or considerable heterogeneity was classified by values < 30 %,
30 % to 60 %, 61 % to 75 %, and > 75 %, respectively [25]. All analyses were performed using STATA v16.1 software (StataCorp, LLC College
Station, Texas, United States).
Results
Search results and population characteristics
From an initial group of 142 studies, seven studies reported data regarding use of
ERAT in 298 patients with appendicitis. Studies with overlapping cohorts were identified
and the most appropriate ones were included in the final analysis. The majority of
patients were males (53.3 % reported in 5 studies) and their mean age was 31 ± 12.39
years (range 1–74).
Average procedure length was 41.1 ± 7.16 minutes with an average hospital length of
stay of 3.93 ± 1.01 days. Average duration of follow up was 14.07 ± 8.75 months. [Table 1] describes the characteristics of the included studies. A schematic diagram of the
study selection process is illustrated in Supplementary Fig. 1.
Table 1
Characteristics of included studies.
|
Study
|
Year
|
Country
|
Type of study
|
Type of center
|
Type of publication
|
No. patients
|
Mean age
|
Male
|
Female
|
|
Kong
|
2021
|
China
|
Prospective
|
Single
|
Manuscript
|
14
|
32.9
|
5
|
9
|
|
Ding
|
2021
|
China
|
Retrospective
|
Single
|
Manuscript
|
70
|
39.9
|
42
|
28
|
|
Kang
|
2020
|
China
|
RCT
|
Single
|
Manuscript
|
36
|
6.74
|
22
|
14
|
|
Chen
|
2019
|
China
|
Prospective
|
Single
|
Abstract
|
101
|
--
|
--
|
--
|
|
Ye
|
2018
|
China
|
Prospective
|
Single
|
Manuscript
|
22
|
39.5
|
9
|
13
|
|
Li
|
2016
|
China
|
Prospective
|
Single
|
Manuscript
|
21
|
36
|
9
|
12
|
|
Liu
|
2015
|
China
|
Retrospective
|
Multi
|
Manuscript
|
34
|
--
|
--
|
--
|
Characteristics and quality of included studies
There were six single-center studies, no population-based, and one multicenter study
included in our final analysis. Four studies included > 30 patients, two studies included > 20
patients, and one study includes > 10 patients. Six studies were published in manuscript
form and one study was published in abstract form.
Quality assessment was performed with the help of the NOS for cohort studies and Cochrane
risk-of-bias tool for RCTs. All seven studies were of good quality and no poor quality
studies were found. Details of quality assessment can be seen in Supplementary Table 1 and Supplementary Fig. 3.
Meta-analysis outcomes
Primary outcomes
The rate of technical success was 99.36 % (95 % CI: 97.61 %, 100.00 %; I2 = 0.0 %; PI: 0.97,1.00) and the calculated pooled rate of clinical success was 99.29 %
(95 % CI: 97.48 %, 100.00 %; I2 = 0.00 %; PI: 0.97,1.00). [Fig. 1] and [Fig. 2] show the Forest Plots for technical and clinical success of ERAT in appendicitis.
Fig. 1 Pooled rates of technical success of ERAT.
Fig. 2 Pooled rates of clinical success of ERAT Figure 1 Pooled rates of technical success
of ERAT.
Secondary outcomes
The calculated pooled rate of AEs was 0.19 % (95 % CI: 0.00 %, 1.55 %; I2 = 0.00 %; PI = 0.00,0.02) with perforation at 0.19 % (95 % CI: 0.00 %, 1.55 %; I2 = 0.00 %; PI = 0.00, 0.02) being the most common AE. [Table 2] describes AEs.
Table 2
Adverse events and recurrence of ERAT.
|
Study
|
Year
|
Total adverse events
|
Perforation
|
Bleeding
|
Obstruction
|
Infection
|
Recurrence
|
|
Kong
|
2021
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Ding
|
2021
|
1
|
1
|
0
|
0
|
0
|
2
|
|
Kang
|
2020
|
0
|
0
|
0
|
0
|
0
|
2
|
|
Chen
|
2019
|
0
|
0
|
0
|
0
|
0
|
13
|
|
Ye
|
2018
|
0
|
0
|
0
|
0
|
0
|
2
|
|
Li
|
2016
|
1
|
1
|
0
|
0
|
0
|
1
|
|
Liu
|
2015
|
1
|
1
|
0
|
0
|
0
|
2
|
ERAT, endoscopic retrograde appendicitis therapy.
Validation of meta-analysis results
Sensitivity analysis
To assess whether any one study had a dominant effect on the meta-analysis, we excluded
one study at a time and analyzed its effect on the main summary estimate. Based on
this analysis, no single study significantly affected the outcome or heterogeneity.
Heterogeneity
Based on Q statistics, and I2 analysis for heterogeneity, no heterogeneity was noted in the analysis of technical
and clinical success or total AEs of ERAT.
Publication bias
Assessment of publication bias was difficult due to the small size of the majority
of included studies, as these were single-arm studies with dichotomous outcomes.
Discussion
Our study demonstrates that ERAT is an effective, minimally invasive procedure that
can be used to diagnose and treat acute uncomplicated appendicitis. This meta-analysis
shows that ERAT has high technical and clinical success rates with a low rate of recurrences
and AEs in patients with acute uncomplicated appendicitis.
Because the shape and size of the appendix varies greatly, it is often challenging to reliably diagnose AA with CT and abdominal ultrasound,
resulting in high negative appendectomy rates [8]
[17]
[19]
[26]
[27]
[28]
[29]. Several studies have demonstrated that endoscopy combined with appendiceal cavity
imaging obtained with ultrasound or x-ray can accurately diagnose AA [10]
[11]
[18]
[19].
The technical and clinical success rates for ERAT in our meta-analysis were 99.36 %
and 99.29 %, respectively. In a recent study, ERAT was directly compared to antibiotic
therapy alone in children with acute uncomplicated appendicitis [10]. ERAT was found to have a higher clinical success rate of 100 % in comparison to
80.9 % in the antibiotics-only cohort. ERAT also led to immediate relief of abdominal
pain faster than antibiotic therapy alone, laparoscopic appendectomy (LA), or open
appendectomy (OA) [10]
[16]
[20]. In two studies, length of hospital stay postoperatively was shorter in the ERAT
cohort as compared to antibiotic therapy alone and laparoscopic/open appendectomy
[10]
[16].
ERAT appears to be safe and carries a low rate of AEs. The overall AE rate in our
meta-analysis was only 0.19 %. Three cases of perforation occurred in our meta-analysis.
One patient required an emergency appendectomy after 48 hours when contrast leakage
into the abdominal cavity occurred during a second ERAT [11]. The second patient was managed successfully with a plastic stent without surgical
intervention following appendicolith removal using an extraction basket [17]. The third case of perforation was thought to be caused by a guidewire injury and
was managed conservatively with antibiotics [16]. The recurrence rate of appendicitis following ERAT was low, with an overall rate
of 6.01 %. The appendix is also now thought to play a role in immune function and
to possibly maintain the colonic flora, favoring the potential benefit of avoiding
an appendectomy [10]
[11].
This meta-analysis has several limitations. Several studies had small sample sizes
and all the studies originated in one country. Due to this limitation, studies with
patients from all age groups and different ERAT techniques were included. In addition,
most of the studies were undertaken at single centers with advanced endoscopists and
the results may not be generalizable. Data regarding head-to-head comparisons with
laparoscopic/open appendectomy were not available. Only one study reported data from
a comparison of ERAT to antibiotics.
Conclusions
In conclusion, ERAT appears to be a minimally invasive treatment option for management
of acute uncomplicated appendicitis with high technical and clinical success and low
AE rates. In addition, it can be used as a tool to supplement diagnosis of AA. Further
studies with RCTs should be performed before it is adopted as an alternative to surgery.
