key: cord-0814621-ck38jt3l authors: Bolia, Rishi; Dhanesh Goel, Akhil; Badkur, Mayank; Jain, Vidhi title: Gastrointestinal manifestations of pediatric coronavirus disease and their relationship with a severe clinical course: A systematic review and meta-analysis date: 2021-05-29 journal: J Trop Pediatr DOI: 10.1093/tropej/fmab051 sha: ec32b35d4b3250f052142dde3559c73c752bdfa6 doc_id: 814621 cord_uid: ck38jt3l BACKGROUND: Data on the gastrointestinal (GI) manifestations of Pediatric Corona Virus Disease (COVID-19) is conflicting and the relationship between GI involvement and the severity of COVID-19 disease has not been evaluated. The objectives of this systematic review was to determine the GI manifestations of pediatric COVID-19 and to evaluate their role as risk factors for a severe clinical course. METHODS: A systematic literature search was carried out in PubMed and Scopus for studies published before December 31, 2020 with information about the GI manifestations of pediatric COVID-19. Patients with a severe and non-severe clinical course were compared using the inverse variance heterogeneity model and odds ratio (OR) as the effect size. A sensitivity analysis was performed if the heterogeneity was high among studies. RESULTS: A total of 811 studies were identified through systematic search of which 55 studies (4369 patients) were included in this systematic review. The commonest GI symptoms were diarrhea—19.08%(95%CI : 10.6–28.2), nausea/vomiting 19.7%(95%CI : 7.8–33.2) and abdominal pain 20.3%(95%CI : 3.7–40.4). The presence of diarrhea was significantly associated with a severe clinical course with a pooled OR of 3.97 (95%CI: 1.80–8.73; p < 0.01). Abdominal pain and nausea/vomiting were not associated with disease severity. CONCLUSIONS: Diarrhea, nausea/vomiting or abdominal pain are present in nearly one-fifth of all children with COVID-19. The presence of diarrhea portends a severe clinical course. Available data suggests that an asymptomatic or mild disease course is more common in the pediatric age-group as compared to adults . However, severe cases and deaths do occur in children too and have been reported worldwide. In a pooled analysis of 27 studies (4857 patients), 4% children had severe disease. (2) A young age and the presence of underlying comorbidities have been documented as risk factors for a severe disease course in children. (1) In adults, the presence of GI symptoms has also been correlated with increased odds of critical disease. (6) However, in the pediatric age group it is unclear whether the presence of gastrointestinal symptoms also portends a severe disease course. Hence, this meta-analysis was conducted to evaluate the frequency of GI symptoms in pediatric COVID-19 and to figure out whether they were a risk factor for severe clinical course of the disease. This systematic review and meta-analysis has been performed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Inclusion and exclusion of studies was planned using the PECO format -Participants, Three reviewers independently extracted data using a predetermined criterion. The following data was extracted from each study: number of patients, study setting, demographic data, gastrointestinal manifestations and number of patients having a severe and non-severe clinical course. Any discrepancy in data extraction was resolved by mutual discussion. The studies reporting the prevalence data were evaluated by the Appraisal tool for Cross-Sectional Studies (AXIS). This tool comprises of a total of 20 items evaluating the various aspects of the methodological quality of the studies pertaining to aims/ objectives, study design, sample size, reference population, representativeness, non-response, appropriateness and validity of risk and outcome variables, approach to statistical significance, completeness of methodology, description and internal consistency of data, synchrony between the methods, results, discussion and conclusion, description of limitation of the study, potential conflicts of interest and adherence to ethical principles. Each item is rated by three options: 'Yes" (Y) -when it meets the description of the evaluation criterion, 'no' (N) -when the particular criterion is not met or 'Unclear' (U) -when there is insufficient information to evaluate a particular criterion. (8) The quality of the studies included in the comparative data analysis was evaluated by the Joanna Briggs Institute (JBI) critical appraisal checklist. The risk of bias was assessed through ten questions that evaluated the comparability of groups, matching, criteria for identifying the groups, validity of measurement tools, uniformity in exposure assessment, approach to confounder identification, appropriateness of length of exposure and appropriateness of statistical analysis used. (9) Individual questions were assessed as Yes, No or Unclear. The inverse variance heterogeneity model has been utilised for ascertaining the summary effect in this meta-analysis. The pooled prevalence of the individual gastrointestinal symptoms -diarrhea, nausea/vomiting, abdominal pain, dysgeusia and anorexia were expressed as proportion and 95%CI. The data was presented in a forest plot. The risk of occurrence of gastrointestinal symptoms in patients with severe as compared to non-severe disease course were described using odds ratios (OR). Heterogeneity between studies was assessed using I 2 values. I 2 values of more than 75% would indicate high heterogeneity. A p value of less than 0.05 was considered statistically significant. Further, sensitivity analysis was performed by excluding each study to investigate the effect on the overall pooled prevalence and heterogeneity. Poor quality and outlier studies were considered for exclusion in sensitivity analysis. Small study effects, which may be due to a publication bias, was investigated by the Luis Furuya Kanamori (LFK) index and DOI plot. A value of LFK index <1 is indicative of no symmetry, between 1 and 2 indicates minor symmetry and more than 2 is indicative of major asymmetry. Meta-analysis was performed using MetaXL softwarev5.3 software (EpiGear International, Sunrise Beach, Australia). A total of 811 records were found using the systematic search strategy. After removing 143 duplicate studies, 668 articles were screened by title and abstract and were excluded if they 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 were not about the COVID-19 (n = 6), did not involve patients in the pediatric age-group (n = 131), did not contain information about the gastrointestinal manifestations of COVID-19 (n = 215), were case reports (n=126), were review articles ( n = 129 ), was a study protocol only ( n = 4), was an erratum ( n =1) or did not involve human subjects ( n = 1). The selection strategy followed is summarised in Figure 1 . Finally, 55 studies were selected for inclusion in this systematic review. (10-64) Seven studies had data comparing severe with non-severe disease course and were included in the meta-analysis evaluating the association of GI symptoms with the severity of the disease course. The characteristics of the 55 studies that were included in the final analysis are summarised in Table 1 The risk of bias assessment of the included studies have been summarised in Supplementary Tables 2 and 3 . The pooled prevalence of diarrhea was 19.08% (95%CI: 10.6% to 28.2%) (Figure 2) . This data was obtained from 49 studies comprising 4008 children. A high degree of heterogeneity (I2 =95%) was found which could not be eliminated on sensitivity analysis The pooled prevalence of nausea/vomiting (40 studies, 3480 patients, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 and 20.3% (95% CI 3.7% to 40.4%) respectively. The I 2 statistic for these respective symptoms was 97% and 98%. Other GI symptoms were recorded only in a handful of the studies. Data regarding anorexia/feeding difficulties was available in 7 studies with a pooled prevalence of 10% (95% CI 0% to 26%), I 2 = 95%, while dysgeusia was reported in only 4 studies and had a prevalence of 3% (95% CI 0% to 7%), I 2 = 66%. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 In the first few published series of COVID-19 patients, the proportion of patients with GI symptoms was low. However, with the spread of the pandemic , this prevalence has increased, probably owing to increasing awareness about the non-respiratory symptoms of the disease among clinicians. The first meta-analysis of the GI manifestations of COVID-19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 admission to the pediatric intensive care unit.(10) On the other hand in a study of 45 children with MIS-C neither of the individual GI symptoms portended a more severe course. (18) On a pooled analysis we found that patients with diarrhea, but not abdominal pain and nausea/vomiting correlated with disease severity. The strength of our meta-analysis is the fact that it includes a large number of patients (55 studies including a total of 4369 patients) who hail from a diverse regional background. Information from observational studies done in fifteen different countries have been included in our analysis and our results are likely a true depiction of the clinical picture of pediatric COVID-19. This is in contrast to the initial reports which consisted of data originating mainly from China. In our analysis, we have also included studies that were not in English. Google Translate®, a free, web-based program was used for the translation. Our meta-analysis is not without limitations. Firstly, a large number of the included studies were retrospective in nature. Secondly, there was a lot of heterogeneity which could not be eliminated on sensitivity analysis. Thirdly, the aim of most of the included studies was primarily to describe the clinical profile of children with COVID-19. It is well known that respiratory symptoms are the most common symptoms of COVID-19 and hence it is possible that the GI manifestations were under-reported in them. Fourthly, As most of the studies included hospital-based data it is conceivable that our estimates represent the prevalence of gastrointestinal manifestations only in children who require hospital admission. We excluded all studies (n=215) that did not contain information about gastrointestinal symptoms, and the absence of information was not assumed to equate that these symptoms were absent. Lastly, the different studies included in this meta-analysis used different definitions to define severe COVID-19 which probably contributed to the heterogeneity that was observed. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 To conclude, our systematic review and meta-analysis has re-affirmed the fact that GI manifestations are common in pediatric COVID-19. Our analysis suggests that the presence of diarrhea probably portends a severe clinical course and there is a need for focussed attention to the care of children who have diarrhea as a symptom of COVID-19. Prospective studies are needed to confirm our findings. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 http://mc.manuscriptcentral.com/tropej Manuscripts submitted to Journal of Tropical Pediatrics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 http://mc.manuscriptcentral.com/tropej Manuscripts submitted to Journal of Tropical Pediatrics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Risk Factors for Severity in Children with Coronavirus Disease 2019: A Comprehensive Literature Review Clinical Features and Outcome of SARS-CoV-2 Infection in Children: A Systematic Review and Meta-analysis Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children Gastrointestinal manifestations of COVID-19 in children: a systematic review and meta-analysis Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis Epidemiology of COVID-19 Among Children in China Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS) Methodological quality of case series studies: an introduction to the JBI critical appraisal tool COVID-19 Gastrointestinal Manifestations Are Independent Predictors of PICU Admission in Hospitalized Pediatric Patients Spanish Pediatric Intensive Care Society working group on SARS-CoV-2 infection. 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