Introduction: COVID-19 mainly affects the respiratory system and leads to flu-like symptoms, which can rapidly evolve to more severe conditions and death. The pediatric age group is susceptible to COVID-19, although the rate of affected patients is lower and most are asymptomatic.

Objective: Analyze the scientific literature regarding COVID-19 clinical manifestations in the pediatric age group.

Method: A systematic review was carried out by searching for articles published between December 1, 2019 and July 28, 2020 in the PubMed®, Scopus, ScienceDirect, Lilacs, MEDLINE® and Cochrane Library databases using the terms “COVID- 19”, “Child”, “Clinical characteristics” and “Hospitalized” and their correlates. Data extraction was done with the use of a standardized form and a descriptive analysis was performed with frequencies and percentages calculations to verify the prevalence of clinical manifestations.

Results: Thirty-two studies were included, and it was observed that fever was the predominant symptom, followed by coughing and diarrhea. Among the other symptoms, sore throat, fatigue, headache, dyspnea/difficulty breathing, runny nose, nasal congestion, pneumonia, expectoration and tachypnea, in addition to gastrointestinal symptoms, stood out. However, the presence of asymptomatic patients was noted in most of the studies analyzed.

Conclusion: The symptoms of COVID-19 in children, although hospitalized, are mild to moderate in the vast majority. Serious cases and those that need intensive care have been observed in few studies, which may be associated with the favorable outcome of COVID-19 in pediatrics.

• COVID-19

• Hospitalized child

• Signs and symptoms

Pamplona EA, da Silva Ferreira BNM, Renan Alex Fernandes de Oliveira RF, da Cunha Dias ML, Gois Ferreira RK, et al. Clinical Manifestations of Pediatric Patients Hospitalized With COVID-19: A Systematic Review. Ann Pediatr Child Health 2021; 9(3): 1231.

In December 2019, the World Health Organization (WHO), was informed about a disease, then of unknown cause, that coursed with severe pneumonia and could lead to death. The disease originated in Wuhan, China, and among the initial cases, it was observed that there was one factor in common: exposure to city’s seafood, fish and live animals market [1]. The cases increased considerably, and, in January 2020, it was declared an international public health emergency, for its seriousness and rapid spread throughout the world. Studies have found that the causative agent of the disease belonged to the coronavirus family, but it was a new presentation of the virus, named SARS-CoV-2 [1,2].

The novel coronavirus mainly affects the respiratory system, and the symptoms course like flu, however, some cases evolve rapidly into acute respiratory distress syndrome (ARDS) and cause death. The most vulnerable age groups, such as children and the elderly, are generally a priority for health services, however, the rate of pediatric patients at the beginning of pandemic was low and most were asymptomatic, which does not mean that children are less susceptible to the virus and that this rate cannot increase in the future [3,4]. Understanding the pathophysiology of the disease, its different clinical manifestations, complications and evolution is essential, especially in an age group that has a vast clinical variation, so that there is better understanding and management of infant morbidity and mortality [5,6]. Therefore, given the current reality and within this perspective, the present systematic review aimed to analyze the scientific literature regarding the clinical manifestations in the pediatric age group.

This is a systematic review of literature, using the guidelines of the Preferred Reporting Items for Systematic Reviews and MetaAnalyzes: The PRISMA Statement [7]. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO), for prior disclosure of the protocol of this study, to reduce the risk of publication bias. The research was carried out through the search of studies published between December 1, 2019 and July 28, 2020, on the PubMed®, Scopus, ScienceDirect, Latin American and Caribbean Literature MEDLINE® and Cochrane Library databases using the MeSH terms “COVID-19”, “Child”, “Clinical characteristics” and “Hospitalized”, as well as their correlates in English and no language filter was used. For association of descriptors the search strategy with the Boolean term AND was used.

Study eligibility

In the search for literature, the PECO 8 strategy was applied in order to guide the formulation of the research question, whereby each letter represents a component of the issue, as shown in Table 1.

The following inclusion criteria was used: publications of original articles (cohort studies, case control studies, case reports, case series and cross-sectional studies), studies with individuals hospitalized patients who tested positive for COVID-19 under the age of 18 years and who described the clinical characteristics in pediatrics. In this stage, the selection of studies was done by four readers reading titles and abstracts and two more reviewers overseeing that the choice of articles adopted the criteria. The exclusion criteria corresponded to: reports and studies of single clinical case, studies with mixed samples (adult and pediatric), and studies that only addressed the clinical characteristics of non-hospitalized children. In addition, duplicate studies were removed. Subsequently, the articles selected were put through the verification of eligibility criteria by two groups, each containing two readers and an independent reviewer responsible for resolving discrepancies between these readers in any of the steps. Articles that presented insufficient information in the abstracts were also previously selected for reading in full. The titles and abstracts of the articles included in the research were recorded in the Mendeley® reference management software.

Methodological Quality Assessment

The methodological quality of the selected observational studies was assessed through the New Castle-Ottawa Scale (NOS) 8, which consists of an instrument of evaluation for cohort and case control studies, composed of 9 items and subdivided into 3 categories: selection of groups (0 to 4 points), comparability (0 to 2 points) and analysis of study exposure or outcome (0 to 3 points), totaling 9 points, which represents high methodological quality. Prospective studies were analyzed by the tool for cohort studies and retrospectives through the tool for case-control studies.

Data Extraction and Analysis

The data extraction was carried out independently by the researchers, through a standardized form prepared by them. Subsequently, the data was inserted into a digital spreadsheet containing information regarding authors, location of study, sample, type of study, aim, data collection instrument and clinical manifestations. To verify the prevalence of clinical manifestations found in the studies included in the sample, a descriptive analysis was performed with calculation of frequencies and percentages.

Initially, 363 articles were identified in the selected databases. Of these, 17 were excluded for being in duplicate. Another 286 were excluded for title and/or abstract, leaving 60 to be analyzed by reading in full where 28 more articles were excluded for not fitting the eligibility criteria. Thus, the sample for the final analysis of this review was composed of 32 articles. The flowchart according to PRISMA 7 can be seen in (Figure 1).

Figure 1 Articles selection diagram.

The studies included in the final sample were evaluated for quality methodology according to the Newcastle-Ottawa Scale 8, where there was a variation of score with a minimum of 4 (four) and a maximum of (9) stars, as described in Table 2.

The data related to the analysis categories used to characterize the articles selected for this systematic review are presented on (Table 3).

Fever was the most prevalent symptom, being present in 100% of the studies, followed by cough (90.6%) and diarrhea (43.8%). Among the other symptoms, there was sore throat, fatigue and headache. With regard to respiratory symptoms, there was a prevalence of dyspnea/difficulty breathing, runny nose, nasal congestion, pneumonia, sputum and tachypnea. In addition to diarrhea, vomiting, abdominal pain, nausea, constipation and feeding difficulties were also cited. Five articles comprehensively described the presence of gastrointestinal symptoms, not specifically reporting what such symptoms was (Table 4).

Other nonspecific symptoms have been reported: arthralgia, liver dysfunction, kidney dysfunction, myocardial dysfunction, loss of taste, malaise, chills, paroxysmal crying, muscle symptoms, CNS symptoms, refractory hypoxia and hypotensive shock, with each of them cited only once among the total number of articles selected. Finally, the occurrence of pediatric patients infected by SARS-CoV-2, but presenting asymptomatic infection, was observed in 13 of the included studies in this review. These asymptomatic patients represented 40.6% of the sample of studies.

The patients in the articles analyzed in this review were hospitalized due to the symptoms of COVID-19, although the vast majority presented mild symptons. The literature shows that pediatric hospitalization rate remains low in comparison to adult patients [41-44], this circumstance is due to the fact that children and young people are less susceptible to infection by the virus in question [45]. In addition, studies show that clinical manifestations are milder in children compared to adults [46-49] and that they have a lower incidence of cardiovascular disease and cerebrovascular disease, suggesting a better prognosis compared to adult patients [50].

In the study developed by Leung et al. [51], with 451 individuals, containing a pediatric and adult population, a significant difference was observed between the groups with regard to the number of symptoms, with a lower incidence in children. In a study with 9 children and 14 adults, the authors suggested that there is a lower number of children infected with SARS-CoV-2 and, when they develop the disease, their general symptoms are significantly milder [52].

Current literature demonstrates that the proportion of severe cases of COVID-19 in neonatal and pediatric population is approximately 6%, with the majority of cases included in the asymptomatic, mild and moderate categories [46]. Towards this finding, in this review, only two studies, Garcia-Salido et al. [17], and Oualha et al [23], aimed to analyze the serious and lethal cases of COVID-19 in pediatrics, totaling 6.25% of featured items. The others found a preponderance of mild clinical manifestations and moderate, in addition to the proportion of asymptomatic individuals discussed above.

Regarding the characterization of the lethal cases of COVID-19 in pediatrics, the study of Oualha et al. [23], which was included in the result of this review, showed that 60% of cases of pediatric deaths were in adolescents older than 14 years and that the association with some type of comorbidity was also present in 60% of deaths. It is importante to point out that the research carried out by Hillesheim et al. [53], in a Brazilian cohort, observed that the second group most lethally affected by the disease is adolescents over 15 years, second only to the group of neonates, corroborating the results of the study described in the result of this review [23]. Also, as an important finding regarding the age range, Dong et al. [46], demonstrated that 10.6% of severe cases are in the age group of less than one year of age.

In a study by researchers at Harvard University in the USA, children were found to carry a much higher Sars-CoV-2 viral load than previously thought, especially in the first two days of infection, demonstrating a significantly higher level of the virus in airways than adults with COVID-19 hospitalized in ICUs [54].

Dong et al [46], when analyzing 728 children who tested positive for the novel coronavirus, found that when correlating the severity of the disease with the age group, children under one year of age developed more severe and critical conditions. In another study that analyzed the profile of deaths and hospital lethality in children infected with SARS-CoV-2, of the 661 deaths, 198 were in children under one year old, representing 28.9% of deaths and a lethality of 14.2% leading in relation to other ages [53].

The children’s immune systems have distinctions that may explain the different clinical manifestations of COVID-19. The innate response in children is stronger, due to a greater number of natural killer cells (NK cells), which are a type of lymphocytes with an important role in fighting viral infections, being the first line of defense against SARS-CoV-2 [55]. One another study examined serum and cell samples obtained from pediatric patients and adults with COVID-19, where it was observed that children express higher levels of interleukin 17A (IL17A), that helps increase the immune system response during viral infection, and gamma interferon (INF-γ) that fights viral replication, unraveling why children have less repercussions when infected by SARS-CoV-2 [56].

Regarding the most prevalent symptoms, there is a recurrent presence of fever associated with the clinical manifestations of hospitalized children, being found in all articles included in this research. Similar to this result, a review of the case series of children and adolescents reveals that fever was among the most prevalent symptoms among patients who were hospitalized [57]. Raba et al. [58], in its systematic review of the clinical manifestations of COVID-19, also found fever as the main marker symptom of SARS-CoV-2 infection in children and adolescents.

As the pandemic progressed, more cases and evidence emerged of manifestations beyond the respiratory kind; among the most prevalent are gastrointestinal. With an important density in pediatrics, as well as in the studies included in this review, the literature shows that symptoms such as vomiting, diarrhea, constipation, pain and abdominal discomfort are present in hospitalized children and adolescents [62,63]. This fact is due to the angiotensin-converting enzyme (ACE2) being abundantly expressed in glandular cells of the gastric, duodenal, intestinal and rectal epitheliums [64].

A less representative number of pediatric cases with neurological repercussions was observed in this review, corresponding to only 9.3% of those included. This finding corroborates the study by Prata-Barbosa et al. [65], who observed only four cases of children with neural symptoms in a total sample of 79 patients. The potential neurological invasion of SARS-CoV-2 is best perceived in adults, in whom the presence of anosmia and ageusia are likely markers of involvement of the nervous system [67].

According to Carvalho et al. [67], only 6% of the children included in their research presented myalgia, with the age group above fourteen years of age most affected. Such finding is in accordance with that found in this review, where only three articles (9.3%), mentioned myalgia as a symptom associated with pediatric COVID-19, with variation of symptom perception from 4.7% to 7.1% in the sample of these studies. Already in Regarding joint pain (arthralgia), only one study mentions the symptom, consistent with the result of Carvalho et al. [67], with only one case reported. The discussion on the transmissibility of asymptomatic pediatric patients has been perpetuating in recent months and some studies have had similar results when children are tested and infection with the new coronavirus is observed, but without the presence of symptoms. Even when positive and symptomatic family clusters occur as the case described by Silva et al. [68], the pediatric age group proved to be a symptomatic in a sample of seven patients, where two children did not progress with symptomatology and five adults presented the infection and classic symptomatology of COVID-19.

The identification of the total number of asymptomatic patients in the general population is importance for the interpretation of the degree of transmissibility of the disease and its progression, in addition to serving to better outline prevention and control strategies for COVID-19 [69]. In pediatrics this becomes an even greater necessity due to the high number of children who present without symptoms or subclinically, but still with transmission potential that can only be detected from IgG tests (immunoglobulin G) [69].

With this review it was analyzed that the symptoms of COVID-19 in children, even when hospitalized, is from mild to moderate in its great majority. The most frequent symptoms found were fever, respiratory and gastrointestinal. Neurological, liver and kidney symptoms were less prevalent. A small amount of studies described patients who needed intensive care, which highlights the favorable prognosis of the disease in the pediatric population.

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