Uncomplicated acute appendicitis – towards optimization of diagnostics, antibiotic management, and treatment costs

Acute appendicitis is the most common reason for acute abdominal pain, currently known to present in two different forms: uncomplicated and complicated acute appendicitis. This difference in appendicitis severity between these two forms can be quite accurately differentiated prior to treatment assessment using computed tomography (CT) imaging. Complicated acute appendicitis most often requires emergency appendectomy. However, recent accumulating evidence has shown antibiotic treatment to be a safe and feasible treatment alternative for uncomplicated acute appendicitis. Furthermore, in uncomplicated acute appendicitis, the overall treatment costs of antibiotics at short-term follow-up are lower compared to surgery. The main aim of this thesis was to evaluate oral (p.o.) antibiotic monotherapy as a first-line treatment for CT-confirmed uncomplicated acute appendicitis by comparing p.o. antibiotic monotherapy to a combination of intravenous (i.v.) followed by p.o. antibiotics in a randomized multicenter non-inferiority clinical trial (APPAC II). The second aim of this study evaluated the overall costs of surgical and antibiotic treatment for uncomplicated acute appendicitis at long-term follow-up of the APPAC randomized controlled trial (RCT) comparing antibiotics with appendectomy. The third aim of this study was to determine whether the radiation dose of the diagnostic CT imaging could be significantly lowered without compromising diagnostic accuracy by using low-dose CT imaging. In the treatment of CT-confirmed uncomplicated acute appendicitis, p.o. antibiotic monotherapy had similar clinical treatment efficacy as a combination of i.v. and p.o. antibiotics with 1-year success rates of 70.2% and 73.8%, respectively. At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. The accuracy of low-dose CT and standard CT was comparable in diagnosing acute appendicitis as well as in differentiating uncomplicated and complicated acute appendicitis. The low-dose CT was associated with a significant radiation dose reduction compared to standard-dose CT.Komplisoitumaton akuutti umpilisäketulehdus – Kohti diagnostiikan, antibioottihoidon ja kustannusten optimointia Akuutti umpilisäketulehdus eli appendisiitti on yleisin akuutin vatsakivun syy. Akuuttia appendisiittia on kahta eri muotoa: lievempi komplisoitumaton ja vaikeampi komplisoitunut akuutti appendisiitti. Nykyään nämä kaksi eri muotoa voidaan erottaa toisistaan tarkasti jo ennen hoidon määrittämistä tietokonetomografiakuvauksen (TT) avulla. Komplisoitunut akuutti appendisiitti vaatii tavanomaisesti välitöntä leikkaushoitoa. Viimeaikaisten tutkimustulosten mukaan antibioottihoito on osoitettu turvalliseksi ja käyttökelpoiseksi hoitovaihtoehdoksi komplisoitumattomassa appendisiitissa. Käytettävissä olevien lyhyen seurantavälin tutkimustulosten mukaan komplisoitumattoman appendisiitin hoidosta antibiootilla aiheutuu vähemmän kustannuksia verrattuna leikkaushoitoon. Tämän väitöskirjatyön tarkoituksena oli tutkia suun kautta otettavaa antibioottihoitoa ensilinjan hoitona komplisoitumattomassa akuutissa appendisiitissa vertaamalla tablettimuotoisen antibioottihoidon tehoa suonensisäisen ja suun kautta otettavan antibioottihoidon yhdistelmään satunnaistetussa non-inferioriteetti-monikeskustutkimuksessa (APPAC II). Lisäksi tutkimme antibioottihoidon ja leikkaushoidon kokonaiskustannuksia pitkän aikavälin seurannassa. Arvioimme myös, voiko appendisiittin diagnostiikassa käytetyn TT-kuvauksen potilaalle aiheuttamaa säderasitusta pienentää heikentämättä kuvauksen diagnostista tarkkuutta. Komplisoitumattoman akuutin appendisiitin hoidossa tablettimuotoinen antibioottihoito oli kliinisesti yhtä tehokas kuin yhdistelmäantibioottihoito, hoidon onnistuessa vuoden seurantajakson aikana 70.2 %:lla tablettimuotoista ja 73.8 %:lla yhdistelmäantibioottihoitoa saaneilla. Viiden vuoden seurannassa antibioottihoidosta aiheutui tilastollisesti merkitsevästi vähemmän kustannuksia verrattuna leikkaushoitoon. Matala-annoksisen ja standardiannos-TT-kuvantamisen tarkkuus oli toisiaan vastaava sekä akuutin appendisiitin diagnosoinnissa että komplisoitumattoman ja komplisoituneen akuutin appendisiitin erottamisessa. Matala-annoskuvantamisesta aiheutui tilastollisesti merkitsevä sädeannoksen pieneneminen verrattuna standardiannoksiseen TT-kuvantamiseen

Appendiceal microbiome in uncomplicated and complicated acute appendicitis: A prospective cohort study

Uncomplicated and complicated acute appendicitis seem to be two different forms of this common abdominal emergency. The contribution of appendiceal microbiota to appendicitis pathogenesis has been suggested, but differences between uncomplicated and complicated appendicitis are largely unknown. We compared the appendiceal microbiota in uncomplicated and complicated acute appendicitis.\nThis prospective single-center clinical cohort study was conducted as part of larger multicenter MAPPAC trial enrolling adult patients with computed tomography or clinically confirmed uncomplicated or complicated acute appendicitis. The microbial composition of the appendiceal lumen was determined using 16S rRNA gene amplicon sequencing.\nBetween April 11, 2017, and March 29, 2019, 118 samples (41 uncomplicated and 77 complicated appendicitis) were available. After adjusting for age, sex, and BMI, alpha diversity in complicated appendicitis was higher (Shannon p = 0.011, Chao1 p = 0.006) compared to uncomplicated appendicitis. Microbial compositions were different between uncomplicated and complicated appendicitis (Bray-Curtis distance, P = 0.002). Species poor appendiceal microbiota composition with specific predominant bacteria was present in some patients regardless of appendicitis severity.\nUncomplicated and complicated acute appendicitis have different appendiceal microbiome profiles further supporting the disconnection between these two different forms of acute appendicitis.\nClinicalTrials.gov NCT03257423.</p

Blood culture positivity in patients with acute appendicitis: A propensity score-matched prospective cohort study

Background and objective: The prevalence of bacteremia in acute appendicitis is unknown. We aimed to assess prevalence and predictive factors of bacteremia in adult patients with appendicitis.Methods: In this prospective propensity score-matched cohort study, patients were recruited as part of one single-center prospective observational study assessing appendicitis microbiology in concurrence with two randomized controlled trials on non-operative treatment of uncomplicated acute appendicitis. All patients evaluated for enrollment in these three trials between April 2017 and December 2018 with both a confirmed diagnosis of appendicitis and available blood culture on admission were included in this study. Potential predictive factors of bacteremia (age, sex, body mass index (BMI), body temperature, C-reactive protein (CRP), leukocyte count, comorbidities, symptom duration, and appendicitis severity) were assessed. Prevalence of bacteremia was determined by all available blood cultures followed by propensity score matching using sex, age, BMI, CRP, leukocyte count, and body temperature of the patients without available blood culture.Results: Out of the 815 patients with appendicitis, 271 patients had available blood culture and the prevalence of bacteremia was 12% (n = 33). Based on propensity score estimation, the prevalence of bacteremia in the whole prospective appendicitis cohort was 11.1%. Bacteremia was significantly more frequent in complicated acute appendicitis (15%; 29/189) compared with uncomplicated acute appendicitis (5%; 4/82) (p = 0.015). Male sex (p = 0.024) and higher body temperature (p = 0.0044) were associated with bacteremia.Conclusions: Estimated prevalence of bacteremia in patients with acute appendicitis was 11.1%. Complicated appendicitis, male sex, and higher body temperature were associated with bacteremia in acute appendicitis.</p

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis: 5-year results of the APPAC randomized clinical trial

BackgroundThe efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis hasbeen established at long-term follow-up with the majority of recurrences shown to occurwithin the first year. Overall costs of antibiotics are significantly lower compared with appendectomyat short-term follow-up, but long-term durability of these cost savings is unclear.The study objective was to compare the long-term overall costs of antibiotic therapy versusappendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitisACuta) trial at 5 years.Methods and findingsThis multicentre, non-inferiority randomized clinical trial randomly assigned 530 adultpatients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotictreatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded,whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis.Between November 2009 and June 2012, 273 patients were randomized to appendectomyand 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher(pCI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899;ppatients did not undergo appendectomy.ConclusionsAt 5-year follow-up antibiotic treatment resulted in significantly lower overall costs comparedwith appendectomy. As the majority of appendicitis recurrences occur within the first yearafter the initial antibiotic treatment, these results suggest that treating uncomplicated acuteappendicitis with antibiotics instead of appendectomy results in lower overall costs even atlonger-term follow-up.</p

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis:5-year results of the APPAC randomized clinical trial

Abstract Background: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years. Methods and findings: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p&lt;0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p&lt;0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy. Conclusions: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up