Uncomplicated acute appendicitis in children: When to operate in the 21st century?
Shyam J. Deshpande, MD, Maureen Banigan, MD, Jayant K. Deshpande, MD, and Justin L. Lockman, MD MSEd
Original article
St Peter SD, Noel-MacDonnell JR, Hall NJ, Eaton S, Suominen JS, Wester T, Svensson JF, Almström M, Muenks EP, Beaudin M, Piché N, Brindle M, MacRobie A, Keijzer R, Engstrand Lilja H, Kassa AM, Jancelewicz T, Butter A, Davidson J, Skarsgard E, Te-Lu Y, Nah S, Willan AR, Pierro A. Appendicectomy versus antibiotics for acute uncomplicated appendicitis in children: an open-label, international, multicentre, randomised, non-inferiority trial. Lancet. 2025 Jan 18;405(10474):233-240. doi: 10.1016/S0140-6736(24)02420-6. Erratum in: Lancet. 2025 Feb 8;405(10477):468. doi: 10.1016/S0140-6736(25)00206-5. PMID: 39826968.
Original article
CODA Collaborative; Flum DR, Davidson GH, Monsell SE, Shapiro NI, Odom SR, Sanchez SE, Drake FT, Fischkoff K, Johnson J, Patton JH, Evans H, Cuschieri J, Sabbatini AK, Faine BA, Skeete DA, Liang MK, Sohn V, McGrane K, Kutcher ME, Chung B, Carter DW, Ayoung-Chee P, Chiang W, Rushing A, Steinberg S, Foster CS, Schaetzel SM, Price TP, Mandell KA, Ferrigno L, Salzberg M, DeUgarte DA, Kaji AH, Moran GJ, Saltzman D, Alam HB, Park PK, Kao LS, Thompson CM, Self WH, Yu JT, Wiebusch A, Winchell RJ, Clark S, Krishnadasan A, Fannon E, Lavallee DC, Comstock BA, Bizzell B, Heagerty PJ, Kessler LG, Talan DA. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. N Engl J Med. 2020 Nov 12;383(20):1907-1919. doi: 10.1056/NEJMoa2014320. Epub 2020 Oct 5. PMID: 33017106.
We’ve all been there: You receive an overnight call from the general surgery resident about another emergency “lap appy” for a 12-year-old with uncomplicated acute appendicitis. But this time, your resident asks you, “Why are we doing these cases in the middle of the night? We often just give antibiotics at my adult hospital. I thought nowadays medical treatment with antibiotics was just as good as surgery?”1 Your astute resident presents you with data from the CODA Trial, a randomized control trial (RCT) published in the NEJM in 2020, demonstrating that medical management of acute appendicitis was non-inferior to appendectomy in adults.1 After an obligatory recital of the adage “children are not just small adults,” you and your resident dig into the most recent medical literature to learn together.
Today’s PAAD comes from the January 2025 edition of the Lancet. In it, St. Peter and colleagues2 present the APPY Trial, a multicenter RCT performed at 11 centers across Canada, the USA, Finland, Sweden, and Singapore, evaluating the treatment of pediatric uncomplicated acute appendicitis via appendectomy or antibiotic-only therapy. The APPY Trial is an open-label, pragmatic, non-blinded, parallel, multicenter, non-inferiority trial. Non-inferiority trials are designed to determine whether a new treatment (e.g., antibiotic-only treatment) is no worse than an existing treatment (i.e., in this case appendectomy). In other words, “Is the new treatment a reasonable alternative to the standard of care?”
The APPY Trial “was designed as a non-inferiority trial because we recognised that although there was no realistic possibility of antibiotics being superior to appendicectomy [in the cure of acute appendicitis], there could be benefits to non-operative treatment that patients and surgeons might be willing to accept if surgery could be avoided.” The trial was performed between 2016 and 2021 and included children 5 to 16 years old with simple, non-perforated appendicitis. Patients were followed during their inpatient stays, as well as with follow-up at 6 weeks and at 12 months.
The primary outcome of the study was treatment failure. In the antibiotic-only group, treatment failure meant need for subsequent appendectomy within 12 months. In the appendectomy group, treatment failure meant a negative appendectomy (i.e., unnecessary surgery) or surgical complication requiring subsequent general anesthesia within 12 months. For the primary outcome, the authors set the non-inferiority margin at 20%; meaning antibiotic-only therapy would be considered non-inferior to appendectomy if the difference in treatment failure between antibiotic-only and appendectomy was ≤ 20 percentage points. Secondary outcomes included adverse events and total length of hospital stay.
What did the authors find? After screening 9988 patients, there were 978 patients initially randomized, after which 42 withdrew consent. Of the remaining 936, 90 were lost to follow-up (65 in the surgical group, and 25 in the antibiotic group) Of the remaining 846 enrolled patients who had data available through the 12-month follow-up, primary treatment failure occurred in 7% of patients (28 of 394) in the appendectomy group and in 34% of patients (153 of 452) in the antibiotic-only group. There do not seem to be any significant pre-randomization differences between groups in Table 1, which includes data about both the initial 936 patients and those who made it to 12-month follow-up, with perhaps one thing: there is a slightly increased rate of fecalith on imaging in the group randomized to antibiotics.
Because the difference in treatment failure between groups was 26.7% (90% CI 22.4–30.9)—which was greater than the prespecified inferiority margin of 20%— the authors concluded that antibiotic-only therapy was found to be inferior to appendectomy in children with acute, uncomplicated appendicitis. Children in the antibiotic-only group also had longer hospital length of stay, with a median of “1.6 days (IQR 1.0–2.6), compared with 1.0 day (0.75–1.7) in the appendicectomy group (p<0·0001).” Interestingly, children in the antibiotic-only group missed fewer days of school and had lower pain scores in the first 14 days after intervention. And despite the differences, the groups had similar rates of family satisfaction at the 12-month follow-up.
The authors muse, “We chose to use a 20% margin but recognised that patients and parents might be willing to accept a margin wider than 20%, whereas many clinicians would only be willing to accept a narrower margin... Despite this result, we suspect that this difference will continue to be interpreted from opposite viewpoints. Those most interested in avoiding an operation will see these data as providing hope, whereas those most interested in avoiding initial treatment failure or recurrence will see the failure rate as unacceptably high.”
But these results are complicated by the authors’ assumption that the “treatment failure” rates would be the same between those with and without complete data (i.e., those lost to follow-up). For example, it is conceivable that the apparent higher rate of loss to follow-up in the appendectomy group is due to the occurrence of complications that were ultimately treated at another healthcare facility. We wonder if the authors would have found non-inferiority had they instead assumed that patients without follow-up were treatment failures.
Overall, our take on these data: unlike for adults, it’s still not clear what is best for children with acute appendicitis. We agree with the authors that, despite their data showing inferiority, different stakeholders may view these results differently. We also note that possibly requiring later surgery may be an acceptable alternative to definite surgery in the present for some families. What do you think? What is your hospital’s practice? Is there reason to investigate further, or are these data adequate to answer the question in your view? Send Myron your thoughts at myasterster@gmail.com and he will post as a Friday Reader Response.
References
1. Flum DR, Davidson GH, Monsell SE, et al. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. The New England journal of medicine 2020;383(20):1907–1919. (In eng). DOI: 10.1056/NEJMoa2014320.
2. St Peter SD, Noel-MacDonnell JR, Hall NJ, et al. Appendicectomy versus antibiotics for acute uncomplicated appendicitis in children: an open-label, international, multicentre, randomised, non-inferiority trial. Lancet (London, England) 2025;405(10474):233–240. (In eng). DOI: 10.1016/s0140-6736(24)02420-6.