COVID-19 is a disease caused by the SARS-CoV-2 coronavirus and the first cases were reported in Wuhan, China, in December 2019.¹ This disease has had serious consequences worldwide due to its rapid spread, so, since it was first identified, multiple investigations have been carried out to establish its clinical-epidemiological profile, which has not been clearly defined yet despite the significant advances in this regard.

In the pediatric population, COVID-19 was first described as a respiratory infection similar to seasonal influenza outbreaks, where most patients present with mild to moderate respiratory symptoms and occasional respiratory failure, and people with comorbidities are affected the most.²

Current data indicate that COVID-19 affects children and young people less frequently and less intensely, which could be explained by the reduced expression of the angiotensin-converting enzyme 2 (ACE2) receptor in this population, as it is used by SARS-CoV2 to enter the host cells from the nasal epithelium.³

In the lungs, SARS-CoV2 can cause alveolar damage by desquamation of pneumocytes, edema with mononuclear inflammatory cell infiltrate, and membrane deposit on the gas-exchange surface, resulting in ground-glass opacities patterns.^4-6

Although respiratory conditions are most commonly observed, COVID-19 may also present with gastrointestinal symptoms such as abdominal pain, vomiting and diarrhea,⁷ rash-like skin lesions, and even Kawasaki syndrome (a systemic vasculitis of unknown origin associated with bacterial or viral infections) as reported in the pediatric population.⁸ Moreover, it has been reported that groups of children present with cardiac involvement, gastrointestinal symptoms, and significantly elevated markers of inflammation 2 to 4 weeks after developing SARS-CoV-2 infection. This form of presentation is known as multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19.⁹

Similarly, laboratory findings are variable and depend on the availability of tests in each hospital facility; for example, variations in blood count, blood chemistry, markers of inflammation and infection, among others, have also been reported.^5,10

In this context, the objective of this review is to estimate the epidemiological profile of pediatric patients with COVID-19, as well as their clinical, laboratory and radiological characteristics.

A living systematic review was carried out after being granted technical approval by the Obstetrics Program Council of the Universidad Central del Ecuador. The study registration and protocol are available at https://osf.io/y43wm and https://osf.io/r8ktv, respectively.

The initial database search yielded 458 results, of which 131 were removed because they were duplicates, 231 were not related to the research subject, 75 did not meet the inclusion criteria, and 8 had poor quality or non-minimum sample compliance (101 patients). Finally, 13 studies were included for full analysis: 1 cross-sectional study, 1 cohort study, and 11 case series, which together described a total of 9 152 patients. Not all variables had the same number of cases, so statistical analyzes were made with the available data. The study selection flowchart is summarized in Figure 1.

Figure 1 Source: Own elaboration.

Table 1 presents a summary of the demographic characteristics of each of the articles included. Sex was described in 9 019 patients and the total number of men affected was 4 867 (53.9%).

Table 1

ID	Author	Average age *	Total patients	Male (%)	Country-region	Type of study	Features	Critical appraisal0/)
1	Lu et al.24	6 years	110	59 (53.63)	China	Case series	Single center	80
2	Xiong et al.25	3 years and 8 months	244	120 (62.17) t	China	Cross-sectional	Single center	75
3	Wu et al.26	84 months (IQR: 18123 months)	148	60 (40.54)	China	Case series	Single center	70
4	Li et al.27	6 years (IQR: 1-9 years)	125	71 (56.8)	China	Case series	Single center	80
5	Dong et al.28	7 years (IQR: 2-13 years)	731	420 (57.45)	China	Case series	Multicenter	80
6	Lu et al.10	6.7 years (R: 1 day - 15 years)	171	104 (60.81)	China	Case series	Single center	80
7	DeBiasi et al.29	9.6 years	177	92 (51.97)	USA Washington, District of Columbia	Cohorts	Single center	75
8	CDC COVID-19 Response Team30	11 years (R: 0-17 years)	2 572	1 408(56.54) *	USA	Case series	Multicenter	70
9	Bellino et al.31	11 years (IQR: 5-15 years)	3 836	1 970 (51.35)	Italy	Case series	Multicenter	70
10	Garazzino et al.32	5 years (IQR: 0.3-9.6 years)	168	94 (55.95)	Italy	Case series	Multicenter	80
11	Armann et al.33	-	128	64 (50)	Germany	Case series	Multicenter	80
12	Gaborieau et al.34	1 year (R: 0.12-10 years)	157	94 (59.87)	France	Case series	Multicenter	80
13	Götzinger et al.35	5 years (IQR: 0.5-12 years)	585	311 (53.16)	Europe	Case series	Multicenter	80

ID=study identification number; R: range; IQR: interquartile range.

Table 2 presents in detail each of the clinical laboratory and radiological variables, with their partial and total values.

Table 2

CRP: C-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactic dehydrogenase.

According to the age group, patients classified as schoolers and adolescents account for almost 60% of those affected. When analyzing the condition of the patients, it was found that the majority were asymptomatic or had mild respiratory infections, followed by moderate infections; conversely, patients with severe infections or a serious/ critical condition represented low percentages (Table 2).

Regarding signs and symptoms, cough and fever were the most frequent and were found in more than half of the patients; other manifestations occurred in a smaller percentage (Table 2).

COVID-19 is a disease that has greatly impacted all the scenarios of human activity.^36-38 Like any infection caused by other coronaviruses such as SARS-CoV (severe acute respiratory syndrome coronavirus) and MERS-CoV (Middle East respiratory syndrome coronavirus), SARS-CoV-2 affects the pediatric population in a smaller proportion.^39,40 However, it has similar clinical presentation and mortality rates than those reported for the first two viruses.

When comparing COVID-19 with seasonal influenza, it is found that the clinical presentation of both diseases is variable and can range from asymptomatic cases, through mild cases, to serious infections. The population at highest risk of influenza virus infection are children, who are also the main transmitters, while, in the case of COVID-19, they seem to be the least affected.⁴¹

According to the results, COVID-19 occurs more frequently in males, which is consistent with the findings observed in adults, where the proportion of affected men is even higher. This increased susceptibility of the male sex may be due to multiple factors (biological and physiological) such as increased expression of the ACE2 receptor blockers or the presence of the double X chromosome to which a protective role is attributed.¹ In this context, it should be borne in mind that, in most regions, it is still men who work the most out of their homes, which increases the likelihood of infection; this greater contact with people outside the home is also typical of schoolchildren and adolescents, which would explain why these age groups are more affected.^4,42,43

Similarly, lockdowns have helped elucidate the source of the infection. In China, for example, the population was confined early, which is why it was established that most children were infected in their household, unlike populations where confinement started late and where most infections occurred is not clear.⁴⁴

Underlying diseases condition susceptibility to infection by or worsening of COVID-19 symptoms. According to the studies analyzed, up to 50% of the severe or critical patients had comorbidities, mainly pulmonary, neurological, cardiovascular, or obesity, which is consistent with the reports in adults.^10,45,46

COVID-19 may present with variable symptoms. In this regard, Wise⁴⁷ analyzed the data obtained from a symptom tracking application and reported that there are six different "types" of COVID-19. Each type is characterized by a group of symptoms that are classified as follows: (i) "flu-like" without fever (headache, hyporexia, cough, odynophagia, myalgia, and chest pain); (ii) "flulike" with fever (headache, hyporexia, anosmia, cough, dysphonia, odinophagia); (iii) gastrointestinal (headache, anosmia, hyporexia, diarrhea, odinophagia, and severe chest pain); (iv) severe level one: fatigue (headache, chest pain, anosmia, cough, fever, and dysphonia; (v) severe level two: confusion (headache, chest pain, myalgia, odinophagia, anosmia, hyperexia, cough, fever, and fatigue); and vi) severe level three: abdominal and respiratory involvement (headache, odinophagia, chest pain, abdomen and muscles, anosmia, hyperexia, cough, fever, dysphonia, fatigue, confusion, respiratory distress, and diarrhea.) The same study reported that patients with clinical symptoms level 4 to 6 are more likely to be admitted to the hospital and need respiratory support,⁴⁷ which also coincides with the reports in the adult population.

In this regard, Xiong et al.²⁵ found that children with COVID-19 and gastrointestinal symptoms are prone to further deterioration of their clinical symptoms and alterations of lab test results. Moreover, several studies have reported the presence of SARS-CoV-2 in children's feces even up to 30 days after infection,⁴⁸ although it is worth mentioning that the fecal-oral route has not yet been determined.⁴⁹

It should be noted that cough and fever are the most common symptoms and that rates of up to 72.2% and 89.1%, respectively, have been reported in adults. In the pediatric population, the percentages are lower, which could be explained by the higher number of patients under 19 years of age who are asymptomatic or present with a mild infection.⁵⁰

Laboratory test results are not conclusive since leukopenia is relatively frequent in viral processes in children;³⁹ however, only lymphopenia yielded results with a constant proportion, even though the number of studies found was not sufficient to estimate its overall proportion. It should be noted that lymphopenia occurs in greater proportion in adults and is considered a critical factor associated with the severity and mortality of the disease.⁵ This may be related to both the characteristics of the immune system and the low percentage of severe/ critical patients reported in the studies analyzed here.

With respect to inflammation and infection markers, the overall proportion of patients with elevated C-reactive protein and procalcitonin levels could not be established in this study. However, it should be noted that the results of both tests may be normal in patients with mild infections and that the elevation of these markers is associated with more severe clinical manifestations or bacterial coinfections.^10,39,45 The same occurs with the elevation of the D-dimer, which is usually accompanied by a systemic inflammatory response and coagulation activation in patients with severe symptoms.^39,51

Lactate dehydrogenase and transaminases (aspartate aminotransferase and alanine aminotransferase) are elevated in infectious or inflammatory processes, and the latter increase even more when the liver is involved. Although the elevation of these enzymes is sometimes non-specific, measuring their increase can help assess systemic involvement when a patient is ill. ^39,45,52

Pulmonary ground-glass opacities were found in 60% of the patients analyzed in the studies included in the present review; however, this same pattern has been described in up to 96.6% of cases in adults.^40,49,50 In both groups, lung injury is most evident in computed tomography.^5,53

The present work was prepared based on the best evidence available up to the date of the review, so it includes quality studies that are mostly multicenter. In addition, Bayesian methods were applied to calculate OR. Nevertheless, its limitations include that all data are reported in retrospective studies; the overall proportion in most variables presented high heterogeneity that may be associated with genetic, geographic or ethnic causes; there was a lack of stratification of the variables according to the different age groups since some symptoms can only be reported by patients older than five years, for example, headache or anosmia; and not all studies presented the variables analyzed and, therefore, the number of observations was not constant. Given these limitations, the results of this study should be contrasted with prospective randomized controlled studies with larger samples and a stricter design.

Clinical and epidemiological characteristics of COVID-19 in pediatric patients cannot yet be accurately described based on the current data. However, the male sex seems to be more affected and lung alterations in imaging studies are more frequent than clinical signs such as cough and fever. Laboratory results are not conclusive and reflect that different organs and systems are affected by the virus.

This meta-analysis was prepared based on the best data available up to the date of the review and on a rigorous analysis, so the data are credible and will serve as the basis for future comparisons between regions or age groups.