Paediatric appendicitis: international study of management in the COVID-19 pandemic

The COVID-19 pandemic had a huge impact on healthcare systems worldwide, forcing policymakers to reorganize hospital resources to prioritize COVID care. Recommendations were made by surgical societies to postpone elective surgery and apply non-operative alternatives if available for surgical diseases1–3. The aim of this multicentre international study was to investigate the impact of the COVID-19 pandemic on paediatric appendicitis, specifically the proportion of children with complex appendicitis, alterations in the diagnostic work-up and treatment strategies, and its outcomes. An international retrospective study was conducted at 40 hospitals from 23 countries (Appendix S1). The study was overseen by an international study steering group (RG/AZ/AP/NH/TW/FM/AG/PA) that developed the study protocol. This study was endorsed by the European Paediatric Surgeons’ Association (EUPSA), which assisted in the recruitment of participating hospitals through the EUPSA Network Office. Principal investigators of participating sites obtained local ethical approval in accordance with local requirements. The study was reported according to the STROBE guidelines4. Patients (aged less than 18 years) treated for acute appendicitis between January 2019 and December 2020 were screened for eligibility. Those who had non-operative treatment without an imaging-confirmed diagnosis of acute appendicitis were excluded. Diagnosis of acute appendicitis was defined by intraoperative and histopathological confirmation of appendicitis, and, in the event of non-operative treatment (Appendix S2), based on clinical, biochemical, and radiological criteria. Local investigators were asked to define the start of the COVID-19 pandemic at their institution based on the start of the interval during which regular healthcare was affected by the pandemic. The COVID group included patients treated between the start of the COVID period and 31 December 2020. The control group consisted of patients treated during the corresponding interval in 2019. To understand healthcare protocols and management strategies for acute appendicitis before and during the pandemic at each centre, all participating sites were asked to complete a survey that was sent on 23 March 2021 (Appendix S3). Variables of interest and their definitions were agreed by the study steering group based on the globally supported core outcome set for studies reporting the treatment of acute simple appendicitis in children5–8. Primary outcomes were the proportions of children treated for complex appendicitis, children who underwent imaging procedures for confirmation of appendicitis, children treated using non-surgical treatment strategies, and complications directly related to treatment. Secondary outcomes and definitions are shown in Appendix S2. Comparative analyses were undertaken by calculating differences in proportions and 95 per cent confidence intervals. Subgroup analyses based on time interval of presentation, age, and region were performed for appendicitis severity and complications. For all subgroup analyses, Bonferroni correction was applied to adjust for multiple testing. Statistical analyses were carried out using SPSS® version 26 (IBM, Armonk, NY, USA). Between January 2019 and December 2020, some 10 655 children were treated for acute appendicitis, of whom 2062 were excluded for the reasons outlined in Appendix S4. Therefore, 8593 patients were included, 4113 in the COVID group and 4480 in the control group. Baseline characteristics were similar in the two groups (Appendix S5). The survey showed that, in the majority of participating centres, non-operative treatment and same-day discharge were not standard care during the pandemic, and that there was no change in referral pathways or shift of patients with complex disease to the participating centres (Appendix S1). In the COVID group, 47.7 per cent of patients were treated for complex appendicitis versus 45.0 per cent in the control group (difference 2.7 (95 per cent c.i. 0.6 to 4.8) per cent; P = 0.014) (Table 1). This increased proportion of complex appendicitis was apparent only during the first 3 months of the pandemic (difference 5.6 (1.8 to 9.3) per cent; P = 0.003, adjusted P = 0.007) and was predominantly caused by an absolute decrease in patients with simple appendicitis. The subgroup analysis based on region showed that the proportion of patients treated for complex appendicitis increased by 3.5 (1.2 to 5.8) per cent in Europe (P = 0.004, adjusted P = 0.020). No differences were found for other continents (Table 2). Diagnostic work-up, treatment, and outcomes Values are n (%) unless otherwise indicated; *values in parentheses are 95 per cent confidence intervals and †values are median (i.q.r.). CD, Clavien–Dindo grade. ‡Chi-Square test, except §Mann-Whitney U test. Diagnostic work-up, treatment, and outcomes Values are n (%) unless otherwise indicated; *values in parentheses are 95 per cent confidence intervals and †values are median (i.q.r.). CD, Clavien–Dindo grade. ‡Chi-Square test, except §Mann-Whitney U test. Subgroup analyses of severity of appendicitis and complications Values are n (%) unless otherwise indicated; *values in parentheses are 95 per cent confidence intervals. †Chi-Square test, with Bonferroni correction. Subgroup analyses of severity of appendicitis and complications Values are n (%) unless otherwise indicated; *values in parentheses are 95 per cent confidence intervals. †Chi-Square test, with Bonferroni correction. In the COVID group, 86.0 per cent of children underwent imaging during diagnostic work-up compared with 84.4 per cent in the control group (difference 1.6 (95 per cent c.i. 0.1 to 3.1) per cent; P = 0.037). During the pandemic, 7.7 per cent of patients had non-operative treatment compared with 7.3 per cent in the control group (difference 0.4 (–0.7 to 1.5) per cent; P = 0.495). Outcomes of non-operative treatment are recorded in Appendix S6. Among those treated surgically, 74.3 per cent in the COVID group and 71.2 per cent in the control group underwent laparoscopic appendicectomy (difference 3.1 (1.2 to 5.1) per cent; P = 0.002) (Table 1). Both the primary and subgroup analyses showed no differences in the number of patients experiencing any complication between the COVID and control groups, nor in the severity of complications. In both groups, intra-abdominal abscess was the most frequent postoperative complication (Tables 1 and 2). This large international study found that the number of patients presenting with simple appendicitis decreased during the first months of the pandemic, resulting in a higher proportion of complex appendicitis than in the control interval. The proportion of patients who had non-operative treatment and the proportion of complications were comparable to those in the control period. These data suggest that the management and outcomes of children with acute appendicitis were relatively unaffected by the pandemic, reflecting the resilience of the participating centres. Several small single-centre studies9–14 have reported contradictory results on the influence of the pandemic on the proportion of patients treated for complex appendicitis; some reported increased proportions of complex appendicitis (7–18 per cent), whereas others could not detect any difference. In the present study, the increased proportion of complex appendicitis seems to be the result of an absolute decrease in patients with simple appendicitis. A possible explanation could be the resolution of mild cases of simple appendicitis in patients who did not seek medical care and recovered spontaneously or were treated with antibiotics by general practitioners15,16. After the first months of the pandemic, proportions of simple and complex appendicitis were comparable to those in the control group, which was predominantly the result of an absolute increase in patients with simple appendicitis. This could be explained by the fact that the threshold for seeking medical care for mild appendicitis possibly decreased after the first few months of the pandemic, as lockdown measures were slowly lifted and COVID-19-related fear declined. These findings are in line with those of other population-based studies17–19 that noted an absolute decrease in both adult and paediatric patients presenting with simple appendicitis early in the pandemic. This international multicentre study is limited by possible information and selection bias, which is inherent to retrospective selection of patients and data collection. Furthermore, the regional subgroup analysis was limited by a skewed distribution, as the majority of patients were included in Europe. Finally, the survey found no shift of patients with complex disease to participating centres, but this might still have occurred. The major strength of this study is the international collaboration and subsequent large sample size of more than 8500 patients. CONNECT collaborative study group: Martin L. Metzelder, Sophie Langer (Medical University of Vienna, Vienna, Austria) Ashrarur R Mitul, Sabbir Karim, Nazmul Islam (Bangladesh Shishu Hospital & Institute, Dhaka, Bangladesh) Anna Poupalou, (Université Libre de Bruxelles (ULB), HUDERF Hospital (Hôpital Universitaire des Enfants Reine Fabiola), Brussels, Belgium) Marc Miserez, Edward Willems (University Hospital Gasthuisberg KULeuven, Leuven, Belgium) Erika V. P. Ortolan, Pedro Luiz Toledo de Arruda Lourenção, (Botucatu Medical School, Unesp, Botucatu, São Paulo, Brazil) Mark Bremholm Ellebæk, Susanna Petersen (Odense University Hospital, University of Southern Denmark, Odense C, Denmark) Janne Suominen, Mikko Pakarinen (New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland) Françoise Schmitt (University Hospital of Angers, Angers, France) Arnaud Bonnard, Louise Montalva, Garance Martin (Robert Debré Children University Hospital, APHP, Paris University, Paris, France) Antonella Nahom di Veroli, Zaki Assi (Soroka Medical Center, Beer Sheva, Israel) Alessio Pini-Prato, Ilaria Falconi (Umberto Bosio Center for Digestive Diseases, The Children Hospital, AO SS Antonio e Biagio e cesare Arrigo, Alessandria, Italy) Daniele Alberti, Giovanni Boroni, Beatrice Montanaro (University of Brescia, Department of Pediatric Surgery- Children's Hospital, Brescia-Italy) Antonino Morabito, Andrea Zulli, Riccardo Coletta (University of Florence-Meyer Children's Hospital, Florence, Italy) Carmelo Romeo, Enrica Antonelli, Francesca Nascimben (Unit of Pediatric Surgery, University of Messina, Messina, Italy) Piergiorgio Gamba, Alberto Sgro (University of Padua, Padova, Italy) Alessandro Raffaele, Maria Ruffoli (Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy) Ivan Aloi, Simone Frediani (Bambino Gesù Children's Hospital, IRCCS, Rome, Italy) Marco Gasparella, Paola Midrio (Ca Foncello Hospital-Treviso, University of Padova, PadovaItaly) Mohit Kakar (Riga Stradins University & Children's Clinical University Hospital. Riga, Latvia) Shireen A Nah, Yohesuwary Gunarasa (Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia) Toni Risteski, Vesna Naunova Cvetanoska, Lazo Jovcheski (Ss. Cyril and Methodius University, Skopje, R. Macedonia) Kjetil Juul Stensrud, Henrik Røkkum, Pål Aksel Næss (Oslo University Hospital, Oslo, Norway) Aline Vaz-Silva, Joana Patena Forte, Pedro F. Morais, Joana Queirós Pereira (Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal) Sanja Sindjic Antunovic, Marija Lukac (University Children’s Hospital, Belgrade, Serbia) Marion Arnold, Martina Ichino, Andrew Victor Bernstein, Hettie le Roux (Red Cross War Memorial Children’s Hospital/University of Cape Town, Cape Town, South Africa) Leopoldo Martinez, Carlos Delgado-Miguel, (La Paz Children's Hospital, Madrid, Spain) Paolo Bragagnini Rodriguez, Paula Salcedo Arroyo, Yurema Gonzalez Ruiz (University Hospital “Miguel Servet”, Zaragoza, Spain) Anna Svenningsson (Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden) Joep PM Derikx, Roel Bakx (Emma Children's Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, The Netherlands) Rene MH Wijnen, Claudia MG Keyzer (Erasmus University Medical Centre -Sophia Children's Hospital, Rotterdam, The Netherlands) Gerda W Zijp, EA Huurman (Juliana Children's Hospital/Haga-Hospital, The Hague, The Netherlands) Wim van Gemert, Olivier Theeuws (Maastricht UMC, Maastricht, Netherlands) Ivo de Blaauw, Sanne MBI Botden, Maja Joosten (Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands) Evert-Jan Boerma, Donald Schweitzer (Zuyderland Medical Centre, Heerlen&Sittard-Geleen, The Netherlands) Osman Uzunlu (Pamukkale University School of Medicine, Denizli, Turkey) Ingo Jester, Ben Martin, Hetal N Patel (Birmingham Children's Hospital, Birmingham, West Midlands, United Kingdom) Dina Fouad, Christine Lam (Southampton Children’s Hospital, Southampton, United Kingdom) Clint D. Cappiello, Carla Lopez, Veronica Natale, Emily Lee (The Johns Hopkins Hospital Bloomberg Children's Center, Baltimore, MD, United States of America) T.W. received a grant from the Swedish Medical Research Council. The Swedish Medical Research Council had no role in any part of the study. This study was endorsed by the EUPSA, and participating hospitals were mainly recruited via the EUPSA Network Office. The authors of the CONNECT study steering group had full access to all data in the study and had final responsibility for the decision to submit for publication. Requests for data sharing will be considered by the study steering group upon written request to the corresponding author. Deidentified participant data will be made available after receipt of a written proposal and a signed data-sharing agreement. Disclosure. The authors declare no conflict of interest. Supplementary material is available at BJS online.

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