Archives of Academic Emergency Medicine. 2022; 10(1): e3 REV I EW ART I C L E Incidence of Pediatric Perforated Appendicitis during the COVID-19 Pandemic; a Systematic Review and Meta- Analysis Gholamreza Motazedian1, Poorya Aryanpoor2, Ehsan Rahmanian3, Samaneh Abiri3, Navid Kalani3, Naser Hatami2, Farhad Bagherian4, Mohammad Etezadpour5, Roohie Farzaneh6, Fatemeh Maleki7, Mahdi Foroughian6, Mojtaba Ghaedi8∗ 1. Plastic & Reconstructive Surgery Department, Shiraz University of Medical Sciences, Shiraz, Iran. 2. Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran. 3. Research center for social Determinants of Health, Jahrom University of Medical Sciences, Jahrom, Iran. 4. Department of Emergency Medicine, Babol University of Medical Sciences, Babol, Iran. 5. Surgery department, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 6. Department of Emergency Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 7. Department of Emergency Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran. 8. Plastic Surgery department, Jahrom University of Medical Sciences, Jahrom, Iran. Received: November 2020; Accepted: November 2021; Published online: 1 January 2021 Abstract: Introduction: COVID-19 has affected the pattern of referral to medical centers and quarantine against COVID- 19 might delay referral and management of surgical emergencies. This study aimed to compare the pooled event rate of pediatric perforated appendicitis before and during the COVID-19 pandemic. Methods: This was a systematic review and meta-analysis study based on the PRISMA guidelines. Scopus, Web of Sciences, and PubMed databases were searched for studies reporting the rate of perforated appendicitis based on the post- appendectomy observations or imaging methods. The Egger bias test and funnel plot were used to detect and depict publication bias. Statistical analysis was performed in Comprehensive Meta-analysis package version 3. Results: Twelve studies were eligible for inclusion in our study. The pooled prevalence of pediatric perforated appendicitis in the pre-COVID era was 28.5% (CI95%: 28.3 to 28.7%) with a heterogeneity of 99%. In the COVID era, the event rate proportion was 39.4% (CI95%: 36.6 to 42.3%) with a heterogeneity of 99%. There was a sig- nificant difference in the subgroup analysis within the pre-COVID and COVID era (P<0.001), showing a higher perforation rate in the COVID era. Conclusion: Our study showed that during the COVID-19 pandemic, the rate of perforated appendicitis has significantly increased in comparison to before the COVID-19 pandemic. Keywords: COVID-19; Appendicitis, Ruptured; Abdomen, Acute Cite this article as: Motazedian G, Aryanpoor P, Rahmanian E, Abiri S, Kalani N, Hatami N, Bagherian F, Etezadpour M, Farzaneh R, Maleki F, Foroughian M, Ghaedi M. Incidence of Pediatric Perforated Appendicitis during the COVID-19 Pandemic; a Systematic Review and Meta- Analysis. Arch Acad Emerg Med. 2022; 10(1): e3. https://doi.org/10.22037/aaem.v10i1.1421. ∗Corresponding Author: Mojtaba Ghaedi; Plastic Surgery Department, Jahrom University of Medical Sciences, Jahrom, Iran. Tel: 009809173222049, Email: ghamojtaba247@gmail.com, ORCID: http://orcid.org/0000-0002-0761- 5898. 1. Introduction Diagnosis and decision-making about some diseases like abdominal pain can be challenging for physicians (1). In surgery, the most common cause of abdominal surgery is acute appendicitis. Appendicitis is a surgical emergency and a common disease that can present with a variety of symp- toms (2). The manifestations of this disease overlap with sev- eral other medical conditions. Sometimes the complexities This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem G. Motazedian et al. 2 and differences in the way it occurs can lead even the most experienced physicians to mistake it for other conditions (3). In some cases, especially in children, the symptoms may be deceptive and difficult to diagnose, and on the other hand, prolongation of the disease may be life-threatening or cause severe complications (4). Therefore, correct and timely di- agnosis of the disease requires experience and special skills. Lack of ability of children to give an accurate history, de- layed diagnosis by parents and physicians, and the presence of nonspecific gastrointestinal disorders are other causes of late diagnosis of acute appendicitis in children (5, 6). Ap- pendicitis in pediatric cases is more likely to rupture, and due to the lack of omentum growth in children, peritonitis is more likely to occur and complications are more common (7). In children under 5 years of age, both the diagnosis of acute appendicitis and the risk of appendix rupture is higher (8). Currently, since COVID-19 has emerged as a pandemic all around the world, some concerns have been raised about the management of surgical emergencies in pediatric cases. COVID-19 has a variety of clinical manifestations, including abdominal pain, which can make it difficult for physicians to differentiate acute appendicitis, and as a result, the risk of perforation of the appendix increases (9). Additionally, the quarantine imposed during the COVID-19 epidemic, as well as the refusal of parents and children to visit hospitals out of fear of getting infected with the virus, could have resulted in the increased rate of perforated appendicitis or its com- plications. This study aimed to compare the pooled event rate of pediatric perforated appendicitis before and during the COVID-19 pandemic. 2. Methods 2.1. Study design and setting This systematic review and meta-analysis study was done based on the Preferred Reporting Items for Systematic Re- views and Meta-analyses (PRISMA) guidelines. We quarried Scopus, Web of Sciences, and PubMed databases for studies irrespective of the study time, limiting results to English ar- ticles, cross-sectional and retrospective or prospective stud- ies using the keywords of Appendicitis, Acute Appendici- tis, Perforated, Perforation, Appendix, Appendectomy, Chil- dren, and Pediatric. The following search strategy was used “(COVID-19[MeSH Major Topic]) AND (Acute Abdomen [MeSH Major Topic]) AND (Appendicitis [Title])) OR (Acute Appendicitis [Title])) OR (Appendectomy [Title])) OR (Perfo- rated [Title])) OR (Perforation [Title]) AND (all child [Filter])” in PubMed. Scopus search strategy was “#1 - TITLE-ABS-KEY (Appendicitis OR Acute Appendicitis OR Appendectomy OR Perforation) #2 - TITLE-ABS-KEY (COVID-19 OR SARS-Cov2 OR Coronavirus) #3 - Pediatric OR children #4 - #1 AND #2 AND #3” and the same with TS function in Web of sciences. Studies reporting the rate of perforated appendicitis based on the post-appendectomy observations or imaging meth- ods were considered eligible to be included in our study if re- porting them in the pediatric age group (under 18 years old). 2.2. Quality assessment The Newcastle-Ottawa Quality Assessment Scale (NOS), which was adapted to measure characteristics of quality rel- evant to population-based studies of incidence, was used to assess the studies’ quality (10). Studies having a low possibil- ity of bias were included. 2.3. Measured outcome Our study outcome was comparing the proportion of per- forated appendicitis within two time periods of the Post COVID-19 era (from December 2019) and pre COVID-19 era (before December 2019). Studies were included from 1995 to 2021. 2.4. Statistical analysis The Cochran Q test (two-test for heterogeneity) was used to assess the heterogeneity of the studies. I2 and its 95% confi- dence interval (CI) were used to calculate the percentage of total heterogeneity to total variability. A Q test with a P<0.1 or an I2 greater than 60% was considered to show signifi- cant statistical heterogeneity. Random-effects models with double arcsine transformations were used. A 2-sided P<05 was considered statistically significant, regardless of the I2 statistic. In order to assess the significant difference in pro- portions between groups in each analysis, we calculated the inter-group P-value; when there was a significant difference, we ran pairwise comparisons and adjusted the level when necessary. A funnel plot was used to depict publication bias. The Egger bias test and the Begg-Mazumdar rank correlation Kendall 2 statistic were used to detect asymmetry. Statisti- cal analysis was performed in Comprehensive Meta-analysis package version 3 and bias possibility was visualized using Review Manager Version 5.4.1. 3. Results As shown in figure 1, there were 6234 articles found in the ini- tial search, conducted by two independent researchers, from which 1745 duplicated articles were removed. Then based on the abstracts, unrelated articles, including review articles, interventional and case-control studies, and studies only on the adult population were excluded from the study. Also, ar- ticles whose abstract or main text was not available were ex- cluded. Finally, 278 potentially related articles were listed for full text review. Twelve studies were eligible to be included in our study. A checklist including the name of the researcher, article title, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e3 year and place of study, sample size, and prevalence of perfo- rated appendicitis was used to collect data (table 1). 8 studies were conducted in COVID era, also containing datasets of be- fore COVID. 9 studies were performed in US, one in Pakistan, one in Germany, and one in UK. The largest sample size be- longed to Cheong LH et al. study with 120117 participants. 3.1. Prevalence of pediatric perforated appen- dicitis The pooled prevalence of pediatric perforated appendicitis in the pre-COVID era was 28.5% (CI95%: 28.3 to 28.7%) with heterogeneity of 99%. In the COVID era event rate proportion was 39.4% (CI95%: 36.6 to 42.3%) with heterogeneity of 99% (p < 0.001; figure 2). Egger’s regression revealed no possibility of publication bias (P-2tailed = 0.458), which was in line with the result of Begg and Mazumdar rank correlation (kendall’s rau=-0.263, P=0.104; figure 3a). The risk of bias in studies and quality of studies, assessed using a modified NOS, are presented in fig- ure 3b. Most studies showed a low risk of bias. 4. Discussion Our study showed that there has been an increase in the rate of perforated appendicitis during the COVID-19 pandemic in comparison to before the COVID-19 pandemic. Difficulty diagnosing the disease usually delays the start of treatment and in many cases leads to perforation. While de- layed referral to a medical center could also be a potential factor leading to perforation; COVID-19 pandemic has de- creased public referral to hospitals due to fear of infection (22). Due to the high mortality rate, appendicitis is on the list of important diseases in children. Considering the rapid progression of this disease in children, the need for timely diagnosis of the disease in order to prevent side effects is emphasized by all surgeons. Despite the existence of radio- logical techniques for diagnosing appendicitis, it is still diffi- cult to diagnose acute appendicitis. Additionally, physicians should also be aware of COVID-19’s gastrointestinal symp- toms that might mimic acute abdomen symptoms (23, 24). In case of ruptured appendicitis, the risk of complications in- creases. Imposing unnecessary surgery can also cause com- plications such as intestinal adhesions (25). Our study indi- cated that during the COVID-19 pandemic, the rate of perfo- rated appendicitis has significantly increased in comparison to before the COVID-19 pandemic. Additionally, other stud- ies have shown that even before the pandemic, there were seasonal variations in acute appendicitis cases (26) and racial factors might also be affecting the disease prevalence (8). Re- search has shown that even in one country, the prevalence of acute appendicitis might change over the years (27). Follow- ing the outbreak of COVID-19 and the responsibility of hos- pitals to provide services to patients with COVID-19, the pro- vision of medical services to other patients was largely shut down and only emergencies continued; that might have led to missed cases of some urgent diseases including acute ab- domen. These patients will suffer if left untreated. There- fore, hospitals must be prepared to accept non-COVID-19 patients. Based on Ojetti et al. study, this issue is not limited to ap- pendicitis. The sharp drop in ED visits during the pandemic might be attributed to fear of the virus, implying that in- dividuals with significant conditions did not seek medical help. Worrying statistics emerged, in particular, about a de- crease in cardiology and neurology admissions. Those pa- tients put off seeking medical help out of fear of being ex- posed to COVID-19, resulting in increased morbidity and mortality (28). We recommend Global community training for dealing with emergencies during the pandemic so that time-critical medical situations are not neglected. 5. Limitations There are many factors affecting the prevalence of perforated appendicitis, such as ethnicity, seasonal variation, and the medical centers’ approaches to acute abdomen, which were not considered in our study. 6. Conclusion Our study showed that the COVID-19 pandemic might have led to an increase in the rate of perforated appendicitis in comparison to the before COVID-19 pandemic. One of the serious health concerns during the pandemic is the state of people’s health due to urgent non-COVID-19 diseases, which covers a wide range of patients including acute abdomen cases. 7. Declarations 7.1. Acknowledgments We would like to thank the Clinical Research Development Unit of Peymanieh Educational and Research and Therapeu- tic Center of Jahrom University of Medical Sciences for pro- viding facilities for this work. 7.2. Conflict of interest The authors have declared that no competing interests exist. 7.3. Funding/Support This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). 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(15) 59 6 2021 March 1 to May 31 2019 US /Rochester, Minnesota Esparaz JR et al. (16) 102 26 2021 March to May 2019 US /Alabama Ali S et al. (17) 112 8 2020 March to May 2019 Pakistan/Peshawar Place R et al. (18) 70 13 2020 March 16 to June 7 2019 US/ Northern Virginia Aarabi S et al. (19) 19019 5282 2011 2000 to 2006 New England Deng Y et al. (20) 31457 10524 2010 1997 US Guagliardo MF et al. (8) 9069 2986 2003 1995 and 1997? US / New York and California Cheong LH et al. (21) 120117 32321 2014 2004 to 2010 US and Canada Schäfer FM et al. (11) b 176 49 2021 2020 Germany (Bavaria) Fisher JC et al. (12)b 55 25 2021 Jan and May 2020 US Gerall CD et al. (13)b 48 7 2021 March to May 2020 US / New York city Theodorou CM et al. (14) b 606 255 2021 2019 vs 2020 US /California Horst KK et al. (15)b 51 14 2021 March 1 to May 31 2020 US / Rochester, Minnesota Esparaz JR et al. (16)b 103 47 2021 March to May 2020 US /Alabama Ali S et al. (17)b 42 23 2021 March to May 2020 Pakistan/Peshawar Place R et al. (18) b 90 35 2021 March 16 to June 7 2020 US/ Northern Virginia N: number. b, same study containing cohorts of both Pre-COVID and post-COVID eras. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e3 Figure 1: PRISMA flow chart of the present study. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem G. Motazedian et al. 8 Figure 2: Forest plot of pooled prevalence of perforated appendicitis in pre-COVID and Post-COVID eras (p < 0.001). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2022; 10(1): e3 Figure 3: Funnel plot of the study and risk of bias. (a) Funnel plot of the study; (b) risk of bias in the included studies based on the modified Newcastle-Ottawa Quality Assessment Scale (NOS). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References