Methods
Protocol and registration
This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.
Eligibility criteria
All studies focusing on the initial nonoperative management and comparing antibiotic treatment with appendectomy for acute nonperforated appendicitis in children were eligible for inclusion.
Commentaries, correspondence, editorials, letters, clinical guidelines, surveys, and case reports, as well as studies reporting nonoriginal data (systematic reviews, meta-analyses, narrative reviews) were excluded.
Studies addressing both adults and children or both perforated and nonperforated appendicitis and that did not report data from nonperforated disease and children separately were excluded. We also excluded all studies reporting data about immune-compromised children because of the potentially worse outcomes.
A systematic search of the literature was performed in Medline via PubMed, Embase, Cochrane and Web of Science in May 2019.
Search strategy
Using Boolean operators AND and OR, we used all possible combination of the following search terms: "acute appendicitis, appendicitis, uncomplicated, noncomplicated, nonperforated, unperforated, conservative, antibiotic, nonoperative, child, children, infant, pediatric, adult”. The search was limited to human subjects and children (0–18 years), but without language or publication year restriction.
Study selection
The online systematic review management program Covidence (
https://www.covidence.org/) was used to coordinate the screening and data collection process. Preliminary screening of all studies on title and abstracts was performed independently by two reviewers (SM and BA) with any disagreement resolved by the senior reviewer (JFS). After initial screening, full-text articles, meeting inclusion criteria, were selected for inclusion.
Data collection process
The data extraction was performed independently by two investigators (SM and BA) after reading the full-text publications. Both researchers extracted data into predefined protocols. The datasets were compared and any irregularities were corrected by a joint assessment among the authors. The final protocol specified 38 data items.
Data items
The main outcomes were the efficacy of nonoperative treatment and the complication rate of both treatment strategies. Efficacy was defined as no need of appendectomy during the initial hospital stay. A third outcome was appendectomy, in children who were discharged from the initial hospital stay, due to recurrent appendicitis or recurrent abdominal pain with normal appendix. Interval appendectomies due to surgeon’s or parents’ choice were also included.
We defined complications as conditions requiring general anesthesia after the initial treatment; perforated appendicitis or peritonitis after nonoperative treatment or postoperative complications requiring invasive intervention. Negative appendectomy was included as a complication in patients undergoing appendectomy as initial treatment.
Additional outcomes were hospital stay during the initial admission and total hospital stay, which included readmission during follow-up.
Summary measures
The summary effects of each respective meta-analysis were presented in forest plots, rendering standardized mean differences (SMD) or odds ratio (OR) with 95% confidence intervals (CI), respectively.
Limitations
One main limitation of this meta-analysis was the heterogenous design of included studies. Inclusion and exclusion criteria, age, symptom duration, and the presence of appendicolith, were different in the included studies. The protocol for treatment with antibiotics, in the nonoperative treatment group, varied between the studies. Several studies were of low quality, with considerable risk for selection bias. There was only one randomized controlled pilot trial available.
Several of the comparative studies used a parent or patient choice design. We appreciate that the opinion of patients and parents is crucial for nonoperative treatment for children with acute appendicitis being a viable treatment option. The balance between optimizing recruitment and achieving acceptability of a randomized controlled trial to participants is a challenge for researchers. To have high external validity, the proportion of the study population of interest who are actually recruited into the randomized controlled trial should be high and representative. But, it is also important to have high internal validity to avoid selection bias, and this is best achieved with a randomized controlled trial. Due to the lack of randomization, and the likelihood of bias toward the less severely ill patients choosing antibiotic treatment, we are not able to assume that the group undergoing appendectomy are in a similar clinical condition using the parent or patient choice design. Only a true randomized controlled trial will minimize the likelihood of these differences influencing trial results. [
33] Another limitation to this meta-analysis is the limited data on long-term follow-up. In children, there are no available long-term data. In adults, a recent 5-year follow-up of the APPAC trial showed that 27% of patients had undergone appendectomy at 1 year and 39% at 5 years, indicating that recurrences occur also in long term [
34].
Conclusions
This systematic review and meta-analysis show that nonoperative treatment of nonperforated acute appendicitis in children is safe and efficient. However, large randomized controlled trials are necessary to compare outcomes with appendectomy. Currently, the authors only treat nonperforated appendicitis with antibiotics as part of an ongoing randomized controlled trial. Patients not included in the trial undergo appendectomy.
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