key: cord-0952661-nh6s8xm3 authors: Toba, Nagham; Gupta, Shreya; Ali, Abdulrahman Y.; ElSaban, Mariam; Khamis, Amar H.; Ho, Samuel B.; Popatia, Rizwana title: COVID‐19 under 19: A meta‐analysis date: 2021-02-25 journal: Pediatr Pulmonol DOI: 10.1002/ppul.25312 sha: 46d819c2b59d9c3a7c638dd2f33b6d26719dac22 doc_id: 952661 cord_uid: nh6s8xm3 BACKGROUND: The coronavirus disease 2019 (COVID‐19) pandemic continues to cause global havoc posing uncertainty to educational institutions worldwide. Understanding the clinical characteristics of COVID‐19 in children is important because of the potential impact on clinical management and public health decisions. METHODS: A meta‐analysis was conducted for pediatric COVID‐19 studies using PubMed and Scopus. It reviewed demographics, co‐morbidities, clinical manifestations, laboratory investigations, radiological investigations, treatment, and outcomes. The 95% confidence interval (CI) was utilized. RESULTS: Out of 3927 articles, 31 articles comprising of 1816 patients were selected from December 2019 to early October 2020 and were defined by 77 variables. Of these studies 58% originated from China and the remainder from North America, Europe and the Middle East. This meta‐analysis revealed that 19.2% (CI 13.6%–26.4%) of patients were asymptomatic. Fever (57%, CI 49.7%–64%) and cough (44.1%, CI 38.3%–50.2%) were the most common symptoms. The most frequently encountered white blood count abnormalities were lymphopenia 13.5% (CI 8.2%–21.4%) and leukopenia 12.6% (CI 8.5%–18.3%). Ground glass opacities were the most common radiological finding of children with COVID‐19 (35.5%, CI 28.9%–42.7%). Hospitalization rate was 96.3% (CI 92.4%–98.2%) of which 10.8% (CI 4.2%–25.3%) were ICU admissions, and 2.4% (CI 1.7%–3.4%) died. CONCLUSION: The majority of pediatric patients with COVID‐19 were asymptomatic or had mild manifestations. Among hospitalized patients there remains a significant number that require intensive care unit care. Overall across the literature, a considerable level of understanding of COVID‐19 in children was reached, yet emerging data related to multisystemic inflammatory syndrome in children should be explored. The novel coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1 has created a global healthcare pandemonium with over 61.8 million cases and 1.4 million deaths reported worldwide as of December 1, 2020. 2 Since its inception in Wuhan, China in December 2019 as a cluster of cases presenting with influenza-like illness, the virus' uncurbed spread has spanned over 218 countries and territories resulting in the World Health Organization (WHO) announcing it as a pandemic on March 11, 2020. 3 The disease presented itself in earlier stages primarily as a respiratory illness with higher morbidity and mortality in older individuals. 4 However, the evolving trends of this novel disease high- May 14, 2020. 8 Our progressing knowledge about the disease in the past year necessitates a data-rich meta-analysis of pediatric COVID-19 to establish statistical significance across these studies and thereby, understanding the validity of the observed parameters. The study aims to describe clinical presentation, laboratory and radiographic findings, treatment modalities and outcomes of pediatric patients under age 19 with COVID-19. Furthermore, the perpetual rapid escalation of cases worldwide and controversies related to re-opening of educational institutes necessitates a more inclusive look into pediatric presentations of COVID-19 to guide health and education policy-making worldwide. The study protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was reported using the PRISMA checklist. 9 The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42020186160 on May 17, 2020. The databases PubMed and Scopus were reviewed from December 1, 2019 to October 3, 2020, to identify all relevant COVID-19 primary publications. The keywords and Medical Subject Headings (MeSH) terms selected included "Novel coronavirus 2019," "COVID-19," and "SARS-CoV-2," and the target population was specified with the terms "pediatric," "children," "infant," "neonate," and "adolescent. " The last search was performed on October 3, 2020 and the search was not limited by language (translation performed with Google Translate) Alternatively, subjects who met the MIS-C criteria as defined by CDC or WHO were also included in the study. 8, 10 The pediatric population was defined by ages 0-18 years (including neonates). The selected articles included variables on demographics, risk factors, clinical manifestations, laboratory investigations, radiological investigations, treatment, and outcomes. Articles were excluded due to the inability to extract pediatric data from adult data separately. The publication types excluded were review articles and studies such as letters, correspondence or comments that had no extractable primary pediatric data. Articles with irrelevant clinical study focus (such as epidemiology, modeling, animal data, pand ost-mortem data) and nonclinical study focus (such as genetics, diagnostic techniques, or virology) were excluded as well. Studies that qualified for initial screening for data extraction, as mentioned above, were further filtered with stringent criteria. The inclusion criteria were optimized for the selection of articles with sufficient data and sample size for data synthesis. checklists were utilized for the critical appraisal of case series and cross-sectional studies. 11 The investigators assigned two points for "Yes," 1 point for "Unclear" and 0 points for "No/Inapplicable." The average score of the two investigators generated the final JBI score. Each checklist had a different cumulative score which was scaled out of 10 (Table 1) . A score more than 7 reflected a high-quality study, 5-7 moderate-quality, and less than 5 low-quality study. the data, the formula, (upper limit-lower limit)/4, was used to extract the standard deviation (SD). The meta-analysis was conducted on Comprehensive Meta-Analysis version 3.3.070 software. The random-effect model was implemented to estimate the pooled prevalence and 95% CI. Pooled percentage, proportion, and corresponding 95% CI were calculated to summarize the weighted effect size for all binary variables. The measure of heterogeneity reported included the Cochran's Q statistics, I 2 index with the level of heterogeneity defined as low less than 25, moderate more than 50, and high more than 75, and the tau square (τ 2 ) test. Publication bias was assessed with a funnel plot and Egger's test. As shown by the literature retrieval flowchart in Figure The total prevalence of co-morbidities associated with pediatric COVID-19 based on 21 studies was 16.9% (CI 11.4%-24.4%). The most common co-morbidities were asthma 3.9% (CI 2%-7.4%) and obesity 3.8% (CI 1.4%-10.1%). Fever was the most prevalent symptom in majority of the papers analyzed (57% with CI 49.7%-64%), followed by cough ( The most commonly encountered white blood cell (WBC) abnormalities were lymphopenia and leukopenia that were present in 13.5% (CI Computed Tomography (CT) of the chest appeared to be the imaging modality of choice over chest x-rays from the meta-analyzed studies in Majority of the patients included in the meta-analysis were hospi- About 42 out of the 77 variables analyzed did not have significant publication bias, denoted by an Egger's p value more than .05. Approximately half of the variables were homogenous based on I 2 index more than 75. This is a meta-analysis of 31 studies with a total of 1816 pediatric patients that was conducted from December 2019 until October 2020. Of these studies 58% originated from China and the remainder from North America, Europe, and Middle East. Our study showed approximately one out of six children had some associated co-morbidity. This was unlike other meta-analyses in the literature which under or infrequently reported comorbidities in pediatric patients. [43] [44] [45] We further dissected the comorbidities and found the most common being history of asthma and obesity. The other co-morbidities associated with COVID-19 presentation in children in our study included history of prematurity, neurological diseases (epilepsy, febrile seizures), congenital heart disease, cancer, and diabetes, which is distinctive from what was found in most adult studies. 44, 46 However, in comparison, adult data had much higher levels of co-morbidity, including hypertension, and diabetes mellitus. 44 Fever and cough were the most reported symptoms in this metaanalysis, which is consistent with findings reported by other metaanalyses including both pediatric and adult data. [43] [44] [45] 47 The adult meta-analysis however, described a much higher proportion of patients complaining of these symptoms. A likely explanation to this difference is the proportion of asymptomatic patients in pediatric populations. Our data shows a much higher proportion of asymptomatic children in comparison to adults but is consistent with other pediatric meta-analyses. 44, 45 Dyspnea was the third most common symptom in our meta-analysis as well as what is reported by Meena et al. 47 However, according to Jutzeler et al., 44 fatigue was the third most common symptom in adults. This may be explained by the fact that pediatric patients will often find it difficult to describe fatigue, whereas it is easier to objectively identify their fever and cough. This study shows that children presented with more upper respiratory findings such as sore throat, nasal congestion, and rhinorrhea. An array of gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain were reported in pediatric patients with COVID-19, however, it was difficult to discern the proportion of these symptoms attributable to the disease process or among side-effects of therapeutic agents used for treatment or a combination of both. This meta-analysis' findings revealed lymphopenia and leukopenia as the most common white cell abnormalities which is similar to other meta-analyses. 45, 47 Among the three analyzed acute phase reactants, procalcitonin was the most highly elevated followed by CRP, then ESR which is also reflected in another meta-analysis. 47 However, the elevation in Procalcitonin was not found in the study by Zhang et al. 45 This meta-analysis shows elevations in LDH, D-Dimer and creatinine kinase which are consistent with Zhang et al. 45 This meta-analysis also shows elevations in LFTs and creatinine which is consistent with Meena et al. 47 Four articles collected data on patients who developed MIS-C, which reported elevations in cardiac biomarkers (Troponin, CKMB, and BNP) as well as IL-6 and IL-10. 16 Co-infections were found in close to one-fourth of patients, which is again a peculiar finding of pediatric COVID-19 and the most common co-infections were bacterial in origin. Ten studies reported patients. Viral co-infections were relatively less frequent, and Influenza A/B and Adenovirus were the most common. Ground glass opacities on CT-scan were the most common radiological finding present in more than a third of patients, resembling previous literature on pediatric 44, 47 Another interesting radiological finding of this meta-analysis was the equal proportion of unilateral and bilateral lesions in CT-scans in children with COVID-19. In contrast, Mantovani et al. 48 and Zhang et al. 45 reported a higher proportion of unilateral involvement than bilateral, while most other meta-analyses have not described other radio findings other than GGOs. 43, 49 This meta-analysis showed reduced manifestations of GGO on CT when compared to adult populations. 44 It is important to note that this study's confidence intervals were narrower and hence relatively more precise than other metaanalyses due to the higher sample size from data-rich articles. Our meta-analysis reports higher than expected death rate (2.4%) compared with surveillance data, but this may be due to sampling and reporting bias within studies. 50 It is possible that our results were confounded by the hetero- must be explored further. Emerging information on the relatively high proportion of asymptomatic cases and its eventual effect on spread of disease will benefit healthcare providers and public health officials in designing appropriate policies. Naming the coronavirus disease (COVID-19) and the virus that causes it WHO Declares COVID-19 a Pandemic Clinical features and outcomes of adults with coronavirus disease 2019: A systematic review and pooled analysis of the literature COVID-19 in children: initial characterization of the pediatric disease Epidemiology of COVID-19 among children in China Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid Accessed Distributed via the CDC Health Alert Network Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Multisystem inflammatory syndrome in children and adolescents with COVID-19: scientific brief The Joanna Briggs Institute approach for systematic reviews A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features Asymptomatic SARS-CoV-2 infection in children: a clinical analysis of 20 cases Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City Children in critical care due to severe acute respiratory syndrome coronavirus 2 infection: experience in a Spanish hospital COVID-19-associated multisystem inflammatory syndrome in children -United States Ethnicity and COVID-19 in children with comorbidities COVID-19: a UK children's hospital experience The epidemiological and clinical characteristics of 81 children with COVID-19 in a pandemic hospital in Turkey: an observational cohort study SARS-CoV-2 infection in children Symptomatic infection is associated with prolonged duration of viral shedding in mild coronavirus disease 2019: a retrospective study of 110 children in Wuhan A single-center, retrospective study of COVID-19 features in children: a descriptive investigation Multisystem inflammatory syndrome associated with SARS-CoV-2 infection in 45 children: a first report from Iran Novel coronavirus infection in febrile infants aged 60 days and younger SARS-CoV-2 infection in infants less than 90 days old Lung ultrasound in children with COVID-19: preliminary findings Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study Clinical features of pediatric patients with coronavirus disease (COVID-19) SARS-CoV-2 infection in infants under 1 year of age in Wuhan City Clinical features of children with SARS-CoV-2 infection: an analysis of 13 cases from Changsha Epidemiologic and clinical characteristics of 10 children with coronavirus disease 2019 in Changsha Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study Clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern China Clinical and immune features of hospitalized pediatric patients with coronavirus disease 2019 (COVID-19) in Wuhan. China Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding Children hospitalized for coronavirus disease 2019 (COVID-19): a multicenter retrospective descriptive study Clinical and epidemiological characteristics of pediatric SARS-CoV-2 infections in China: A multicenter case series The prevalence of symptoms in 24 COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: A systematic review and meta-analysis What we know so far about Coronavirus Disease 2019 in children: a meta-analysis of 551 laboratory-confirmed cases Clinical characteristics of children With COVID-19: a meta-analysis Clinical features and outcome of SARS-CoV-2 infection in children: a systematic review and meta-analysis Coronavirus disease 2019 (COVID-19) in children and/or adolescents: a meta-analysis Clinical characteristics of COVID-19 in children: a systematic review Hospitalization rates and characteristics of children aged<18 years hospitalized with laboratory-confirmed COVID-19 -COVID-NET, 14 States How to cite this article COVID-19 under 19: A meta-analysis The authors would like to thank Dr. Tom Loney for his guidance and Mr. Saad Syed for his early contributions.