Outcomes after appendectomy in children with acute appendicitis treated at a tertiary paediatric centre: results from a retrospective cohort study.

PURPOSE: In general, an appendectomy is presumed to have a limited burden of disease. However, in current literature, reported complication rates vary. This study aims to provide additional insights in the incidence of post-appendectomy complications in children with acute appendicitis. METHODS: This retrospective cohort study included children (0-17 years old) that underwent appendectomy at our tertiary referral centre for suspected acute appendicitis (January 2011-December 2018). Children referred to our centre, and those that underwent non-operative treatment were excluded. Post-appendectomy complications were recorded from electronic medical charts using predefined definitions and classified as severe (Clavien-Dindo III-IV) or less severe (Clavien-Dindo I-II). RESULTS: A total of 131 children were included. Simple and complex appendicitis was diagnosed in 66 (50%) and 60 (46%) children, respectively. A non-inflamed appendix was seen in five (4%) children. One or more complications were identified in 33 (25%) patients. Eight (12%) children with simple appendicitis developed a complication, three of these were severe. In children with complex appendicitis, 23 (38%) children developed a complication, 14 of these were severe. CONCLUSION: This study shows a high rate of complications compared with current literature, both in children with simple and complex appendicitis. This is probably the result of our definition of complications and being a tertiary referral centre receiving more severe appendicitis cases. However, these results still show that appendectomy is not always a routine procedure with only few complications. Substantiating the need to keep optimizing treatment for children with appendicitis.

Accuracy of ultrasonography for differentiating between simple and complex appendicitis in children.

PURPOSE: Accurate differentiation between simple and complex appendicitis is important since differences in treatment exist. This study aimed to assess the accuracy of ultrasonography in differentiating between simple and complex appendicitis. METHODS: Data from children aged < 18 years who underwent appendectomy between the 1st of January 2013 and the 1st of January 2018 were analyzed retrospectively. Ultrasonography reports of eligible children were divided into simple (test negative) and complex appendicitis (test positive) based on predefined criteria and compared to a gold standard (a combination of predefined perioperative and histopathological criteria). Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated to measure ultrasonographic accuracy in differentiating between simple and complex appendicitis. RESULTS: 176 children were eligible for inclusion. The mean age at the time of operation was 10.1 ± SD 4.6 years. 84 (47.7%) children had simple appendicitis and 92 (52.3%) had complex appendicitis. The use of ultrasonography yielded a sensitivity: 46%, specificity: 90%, PPV: 84%, and NPV: 60%. CONCLUSION: Ultrasonography as standalone modality is not suitable for differentiating between simple and complex appendicitis in children. To improve preoperative differentiation, other variables such as clinical signs and laboratory data are necessary in conjunction with ultrasonography findings.

Management of appendiceal mass and abscess in children; early appendectomy or initial non-operative treatment? A systematic review and meta-analysis.

BACKGROUND: Appendiceal mass and abscess and its treatment are associated with significant morbidity and high costs. Still, the optimal treatment strategy is the point of debate. Therefore, this systematic review and meta-analysis aimed to compare overall complications between initial non-operative treatment (NOT) and early appendectomy (EA) in children with appendiceal mass and/or abscess. METHODS: Pubmed and Embase were searched. Only randomized controlled trials and prospective or historical cohort studies that compared NOT with EA in children with appendiceal mass or abscess in terms of complications were eligible for inclusion. Risk of bias was assessed. Primary outcome was the overall complication rate. Secondary, length of stay and readmission rate were investigated. A meta-analysis of overall complications associated with both treatment strategies was performed. RESULTS: 14 of 7083 screened studies were selected, including 1022 children in the NOT group and 333 in the EA group. Duration of follow-up ranged between four weeks and 12 years. Risk of bias was moderate in four and serious in 10 studies. NOT was associated with a lower overall complication rate (risk ratio (RR) 0.37 [95% confidence interval (CI) 0.21-0.65]). However, NOT led to increased length of stay (mean difference varied between 0.2 and 8.4 days) and higher readmission rate (RR 1.75 [95%CI 0.79-3.89]), although not significantly. Interval appendectomy after NOT was performed as a routine procedure in all but one study. This study found a recurrence rate of 34% in a group of 38 patients during a follow-up period of 3.4 ± 1.7 years. CONCLUSION: NOT may reduce the overall complication rate compared to EA, but the evidence is very uncertain. As evidence is scarce, and of low level, and heterogeneity between studies is substantial, the results should be interpreted with caution. Large prospective studies are needed to determine the optimal treatment strategy for children with appendiceal mass and/or abscess.

The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi-center study.

INTRODUCTION: In early sepsis stages, optimal treatment could contribute to prevention of progression to severe sepsis. Therefore, we investigated if there was an association between time to antibiotics and relevant clinical outcomes in hospitalized emergency department (ED) patients with mild to severe sepsis stages. METHODS: This is a prospective multicenter study in three Dutch EDs. Patients were stratified into three categories of illness severity, as assessed by the predisposition, infection, response, and organ failure (PIRO) score: PIRO score 1 to 7, 8 to 14 and >14 points, reflected low, intermediate, and high illness severity, respectively. Consecutive hospitalized ED patients with a suspected infection who were treated with intravenous antibiotics were eligible to participate in the study. The primary outcome measure was the number of surviving days outside the hospital at day 28 which was used as an inverse measure of hospital length of stay (LOS). The secondary outcome measure was 28-day mortality, taking into account the time to mortality. Multivariable Cox regression analysis was used to estimate the association between time to antibiotics and the primary and secondary outcome measures corrected for confounders, including appropriateness of antibiotics and initial ED resuscitation, in three categories of illness severity. RESULTS: Of the 1,168 included patients, 112 died (10%), while 85% and 95% received antibiotics within three and six hours, respectively. No association between time to antibiotics and surviving days outside the hospital or mortality was found. Only in PIRO group 1 to 7 was delayed administration of antibiotics (>3 hours) associated with an increase in surviving days outside the hospital at day 28 (hazard ratio: 1.46, 95% confidence interval: 1.05 to 2.02 after correction for potential confounders). CONCLUSIONS: In ED patients with mild to severe sepsis who received antibiotics within six hours after ED presentation, a reduction in time to antibiotics was not found to be associated with an improvement in relevant clinical outcomes.

Management and outcome of high-risk neuroendocrine tumors of the appendix in children; A systematic review.

This study systematically reviewed the literature to investigate the value of secondary surgery for children with a high-risk neuroendocrine tumor (NET) of appendix. A systematic search was performed in PubMed, Embase and Web of Science. All randomized controlled trials, cohort studies, and case series reporting on the management and outcomes of patients (<20 years) with a histopathologically proven NET of the appendix were eligible for inclusion. Two authors independently selected eligible articles, assessed risk of bias, and extracted data. The outcomes of patients with a high-risk NET treated with secondary surgery were compared to those treated without secondary surgery. Primary outcomes were recurrence rate and disease-free survival. The literature search yielded 667 articles, of which 29 were included. These studies reported on 1112 patients, of whom 145 (13%) had high-risk NET. Heterogeneity between studies was large and risk of bias was serious in 26 and moderate in three studies. Secondary surgery after primary appendectomy was performed in 64 of 145 patients (44%). Length of follow-up ranged between 0 and 612 months. In both treatment groups no recurrences were reported, and thus disease-free survival was 100%. Based on current literature, the value of secondary surgery for pediatric high-risk NET of the appendix may be questioned. However, evidence is scarce, of low-quality, and heterogeneity between studies is large. Large international studies with adequate follow-up are needed to generate high-quality evidence on this topic.

Trends in Simple and Complex Appendicitis in Children and the Potential Correlation to Common Viral Pathogens-A Retrospective Cohort Study between 2010 and 2019 in The Netherlands.

The aim of this study was to evaluate the annual, seasonal and monthly trends in children with simple and complex appendicitis and their correlation to common viral pathogens in the Netherlands. A consecutive multicenter retrospective cohort study was performed between 2010 and 2019 including children (<18 years) surgically treated for appendicitis. The primary outcome was the distribution of children with simple and complex appendicitis per year, season and month. Relevant seasonal variation was defined as ≥5%. The secondary outcome was a positive correlation of the number of patients with simple and complex appendicitis to common viral pathogens (data anonymously provided by the Dutch Working Group on Clinical Virology from the Dutch Society for Clinical Microbiology (NVMM)). In total, 896 patients were included: N = 524 (58%) patients with simple and N = 372 (42%) with complex appendicitis. Of the children aged 0-5 years, 81% had complex appendicitis, versus 38% in 6-18 years (p < 0.001). An overall decline was demonstrated for both simple and complex appendicitis between 2010 and 2019. No seasonal variation was found for simple appendicitis. For complex appendicitis, the highest number of patients was found in spring, and lowest in summer (N = 372, spring 28.2 ± 5.1% versus summer 21.0 ± 5.8%, p = 0.011), but the variance was regarded as not relevant (<5% from baseline). A positive correlation was found between complex appendicitis with Adenovirus 40.41 (R = 0.356, 95%CI 0.045-0.604, p = 0.026) and simple appendicitis with Adenovirus NON 40.41 (R = 0.332, 95%CI 0.019-0.586, p = 0.039), but these correlations did not remain significant after a Bonferroni correction (p < 0.003). In conclusion, we found no relevant seasonal variation for simple or complex appendicitis, nor positive correlation with common viral pathogens.

Predictive scoring systems to differentiate between simple and complex appendicitis in children (PRE-APP study).

BACKGROUND: Several clinical prediction rules have been developed for preoperative differentiation between simple and complex appendicitis in children, as potential treatment strategies differ. This study aimed to externally validate applicable clinical prediction rules that could be used to differentiate between simple and complex appendicitis in children. METHODS: Potential clinical prediction rules were identified by a scoping review of the literature. Clinical prediction rules applicable in our daily practice were subsequently externally validated in a multicenter historical cohort consisting of 1 tertiary center and 1 large teaching hospital. All children (<18 years old) with histopathologically confirmed acute appendicitis between 2013 and 2020 were included. Test results of clinical prediction rules were compared to the gold standard of either simple or complex appendicitis consisting of predefined perioperative and histopathological criteria. Areas under the receiver operating characteristic curves were determined for the selected clinical prediction rules. Areas under the receiver operating characteristic curve >0.7 were considered acceptable and potentially useful. RESULTS: In total, 31 clinical prediction rules were identified, of which 12 could be evaluated in our cohort consisting of 550 children. The main reason to exclude clinical prediction rules was the use of variables that were not routinely measured in our cohort. In our cohort, 208/550 (38%) were diagnosed with complex appendicitis according to the gold standard. Clinical prediction rules with areas under the receiver operating characteristic curve >0.7 were: Gorter (0.81), Bogaard (0.79), Bröker (0.79), Graham (0.77), Hansson (0.76), BADCF (0.76), and Eddama (0.75). CONCLUSION: In this study, clinical prediction rules consisting of a combination of clinical and objective variables had the highest discriminative ability. External validation showed that 7 clinical prediction rules were potentially useful. Integration of these clinical prediction rules in daily practice is proposed to guide decision making regarding treatment strategies.

Identification of the optimal treatment strategy for complex appendicitis in the paediatric population: a protocol for a multicentre prospective cohort study (CAPP study).

INTRODUCTION: In daily practice large heterogeneity in the treatment of children with complex appendicitis exists. Complex appendicitis can be divided into two subtypes; complex appendicitis with and without appendiceal mass and/or abscess. As complex appendicitis is associated with high morbidity and costs, identification of the optimal treatment strategy is essential. In this article, we present the study protocol for the CAPP (Complex Appendicitis in the Pediatric Population) study. METHODS AND ANALYSIS: This nation-wide, multi-centre, comparative, non-randomised prospective cohort study includes all children <18 years old with a preoperative suspicion of complex appendicitis, which is based on imaging confirmed acute appendicitis and predefined criteria regarding the severity of appendicitis. Eligible patients are recruited in more than 30 hospitals. Open appendectomy will be compared with laparoscopic appendectomy for children without appendiceal mass and/or abscess and initial non-operative treatment (ie, intravenous antibiotics with or without percutaneous drainage) to direct appendectomy for children with appendiceal mass and/or abscess. Based on historical data supplied by the participating hospitals and an inclusion period of 2 years and 9 months, a sample size of 1308 patients is aimed. Primary outcome is the proportion of patients experiencing any complication at 3 months follow-up. Reported complications will be assessed by an independent adjudication committee. Secondary outcomes include, but are not limited to, quality of life, and (in)direct costs. To adjust for baseline differences and selection bias, outcomes will be compared after propensity score analysis (inverse probability weighting and stratification). ETHICS AND DISSEMINATION: The Medical Ethics Review Committee of the Amsterdam UMC, location AMC, declared that the Medical Research involving Human Subjects Act (WMO) did not apply to this study. Therefore, no official approval was required by national law. Study results will be presented in peer-reviewed scientific journals and at (inter)national conferences. TRIAL REGISTRATION NUMBERS: NCT04755179; NL9371.

The Management of Post-appendectomy Abscess in Children; A Historical Cohort Study and Update of the Literature.

Introduction: Recent studies have shown that specific cases of post-appendectomy abscess (PAA) in children could be treated conservatively. However, due to the lack of high-quality evidence, choice of treatment still depends on preferences of the treating surgeon, leading to heterogeneity in clinical practice. Therefore, we aimed to provide an update of recent literature on the management of PAA in children and subsequently evaluate the outcomes of a large multicenter cohort of children treated for PAA. Methods: A literature search was performed in Pubmed and Embase, selecting all randomized controlled trials, prospective and retrospective cohort studies, and case series published from 2014 and onward and reporting on children (<18 years) treated for a PAA. Subsequently, a historical cohort study was performed, including all children (<18 years) treated for a radiologically confirmed PAA between 2014 and 2021 in a tertiary referral center and two large peripheral centers. Medical charts were reviewed to compare non-invasive (i.e., antibiotics) and invasive (i.e., drainage procedures) treatment strategies. Primary outcome was the success rate of treatment, defined as no need for further interventions related to PAA or its complications. Results: The search yielded 1,991 articles, of which three were included. Treatment success ranged between 69-88% and 56-100% for non-invasive and invasive strategies, respectively. Our multicenter cohort study included 70 children with a PAA, of which 29 (41%) were treated non-invasively and 41 (59%) invasively. In the non-invasive group, treatment was effective in 21 patients (72%) compared to 25 patients (61%) in the invasive group. Non-invasive treatment was effective in 100% of unifocal small (<3 cm) and 80% of unifocal medium size PAA (3-6 cm), but not effective for multiple abscesses. Conclusion: Non-invasive treatment of especially unifocal small and medium size (<6 cm) PAA in children seems to be safe and effective. Based on these results, a standardized treatment protocol was developed. Prospective validation of this step-up approach-based treatment protocol is recommended.

Ruling out Appendicitis in Children: Can We Use Clinical Prediction Rules?

PURPOSE: To identify available clinical prediction rules (CPRs) and investigate their ability to rule out appendicitis in children presenting with abdominal pain at the emergency department, and accordingly select CPRs that could be useful in a future prospective cohort study. METHODS: A literature search was conducted to identify available CPRs. These were subsequently tested in a historical cohort from a general teaching hospital, comprising all children (< 18 years) that visited the emergency department between 2012 and 2015 with abdominal pain. Data were extracted from the electronic patient files and scores of the identified CPRs were calculated for each patient. The negative likelihood ratios were only calculated for those CPRs that could be calculated for at least 50% of patients. RESULTS: Twelve CPRs were tested in a cohort of 291 patients, of whom 87 (29.9%) suffered from acute appendicitis. The Ohmann score, Alvarado score, modified Alvarado score, Pediatric Appendicitis score, Low-Risk Appendicitis Rule Refinement, Christian score, and Low Risk Appendicitis Rule had a negative likelihood ratio < 0.1. The Modified Alvarado Scoring System and Lintula score had a negative likelihood ratio > 0.1. Three CPRs were excluded because the score could not be calculated for at least 50% of patients. CONCLUSION: This study identified seven CPRs that could be used in a prospective cohort study to compare their ability to rule out appendicitis in children and investigate if clinical monitoring and re-evaluation instead of performing additional investigations (i.e., ultrasound) is a safe treatment strategy in case there is low suspicion of appendicitis.

Non-invasive tumor genotyping using radiogenomic biomarkers, a systematic review and oncology-wide pathway analysis.

With targeted treatments playing an increasing role in oncology, the need arises for fast non-invasive genotyping in clinical practice. Radiogenomics is a rapidly evolving field of research aimed at identifying imaging biomarkers useful for non-invasive genotyping. Radiogenomic genotyping has the advantage that it can capture tumor heterogeneity, can be performed repeatedly for treatment monitoring, and can be performed in malignancies for which biopsy is not available. In this systematic review of 187 included articles, we compiled a database of radiogenomic associations and unraveled networks of imaging groups and gene pathways oncology-wide. Results indicated that ill-defined tumor margins and tumor heterogeneity can potentially be used as imaging biomarkers for 1p/19q codeletion in glioma, relevant for prognosis and disease profiling. In non-small cell lung cancer, FDG-PET uptake and CT-ground-glass-opacity features were associated with treatment-informing traits including EGFR-mutations and ALK-rearrangements. Oncology-wide gene pathway analysis revealed an association between contrast enhancement (imaging) and the targetable VEGF-signalling pathway. Although the need of independent validation remains a concern, radiogenomic biomarkers showed potential for prognosis prediction and targeted treatment selection. Quantitative imaging enhanced the potential of multiparametric radiogenomic models. A wealth of data has been compiled for guiding future research towards robust non-invasive genomic profiling.

Unexpected findings after surgery for suspected appendicitis rarely change treatment in pediatric patients; Results from a cohort study.

BACKGROUND: To determine if non-operative treatment is safe in children with acute appendicitis, we evaluated the incidence of unexpected findings after an appendectomy in children, and the influence they have on subsequent treatment. METHODS: A historical cohort study (January 2004-December 2014) was performed including children, aged 0-17 years, who underwent an appendectomy for the suspicion of acute appendicitis. Patients were divided based upon histopathological examination. Unexpected findings were reviewed, as well as the subsequent treatment plan. RESULTS: In total 484 patients were included in this study. In the overall group, unexpected findings were noted in 10 (2.1%) patients of which two patients intra-operatively with a non-inflamed appendix (Ileitis terminalis N=1 and ovarian torsion N=1) and in 8 patients on histopathological examination. The latter group consisted of 4 patients with concomitant simple appendicitis (parasitic infection N=3 and Walthard cell rest N=1), two with concomitant complex appendicitis (carcinoid N=1 and parasitic infection N=1) and two patients with a non-inflamed appendix (endometriosis N=1 and parasitic infection N=1). Treatment was changed in 4 patients (<1%). CONCLUSIONS: Results from this study corroborate the safety of non-operative strategy for acute simple appendicitis, as the occurrence of unexpected findings was low, with extremely few necessary changes of the treatment plan because of serious findings. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level 2 (retrospective cohort study).