COVID-19 in Children: Where do we Stand?

From the beginning of the coronavirus disease 2019 (COVID-19) pandemic it became evident that children infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain mostly asymptomatic or mildly symptomatic. We reviewed the epidemiologic and clinical features of children with SARS-CoV-2 infection. The true prevalence of asymptomatic SARS-CoV-2 infection is most likely underestimated, as asymptomatic children are less frequently tested. Serologic surveys indicate that half of children tested positive for SARS-CoV-2 report no symptoms. Anosmia/ageusia is not frequent in children but it is the strongest predictor of a positive SARS-CoV-2 test. In general, children with COVID-19 are at lower risk of hospitalization and life-threatening complications. Nevertheless, cases of severe disease or a post-infectious multisystem hyperinflammatory syndrome named multisystem inflammatory syndrome in children (MIS-C) have been described. Rarely children with severe COVID-19 develop neurologic complications. In addition, studies indicate that school closures have a limited impact on SARS-CoV-2 transmission, much less than other social distancing measures. The past months new SARS-CoV-2 variants emerged with higher transmissibility and an increased impact on morbidity and deaths. The role of children in the transmission dynamics of these variants must be elucidated. Lastly, preliminary results from COVID-19 vaccine trials indicate very good efficacy and tolerability in children. Very recently the United States Centers for Disease Control and Prevention and other public health authorities recommend vaccination of children 12 years or older to protect them but mostly to contribute to the achievement of herd immunity.

Introduction

At the end of 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei province of China. The virus spread quickly around the world causing a global pandemic of a disease named coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) (1). In the early stages of the COVID-19 pandemic the proportion of confirmed cases among children was relatively small and it was thought that children were rarely affected by SARS-CoV-2 (2., 3., 4.). Subsequent studies have consistently shown that children and adolescents are susceptible to SARS-CoV-2 infection, yet a large percentage of children are either asymptomatic or pre-symptomatic, therefore the true incidence of infection is underestimated due to the low rate of testing in children (5).

In general, children with COVID-19 present with milder symptoms and are at lower risk of hospitalization and life-threatening complications (6). Nevertheless, cases of severe disease or children developing a post-infectious multisystem hyperinflammatory syndrome named multisystem inflammatory syndrome in children (MIS-C) have been described (7,8). The risk of transmission from an asymptomatic individual with SARS-CoV-2 infection is less than the risk from a symptomatic individual (9). Hence, early studies suggested that children, due to their milder symptoms, do not contribute much to the spread of SARS-CoV-2. However, more recent studies raise concerns that children could be capable of spreading the infection (10).

In this article we review the epidemiologic and clinical features of children infected with SARS-CoV-2. To understand the role of children in the spread of SARS-CoV-2, we investigate the ways through which children have been infected and the transmission chain of SARS-CoV-2. The role of schools in virus transmission and the epidemiological consequences of school closure are also reviewed.

Methods

The PubMed was searched for articles published through March 25, 2021, using combinations of the following words: COVID-19, SARS-CoV-2, children, pediatric, adolescents, infants, and school. We read the abstracts of a total of 101 articles and selected 78 articles based on their relevance to the topics discussed. In addition, information from 8 official public health websites was used. We also added 3 articles on children's vaccination against COVID-19. Overall, 89 articles were included in the review. Children were defined as persons ≤18 years old.

Rate of Children Infected by SARS-CoV-2

In surveillance studies from various countries, children typically accounted for up to 2% of laboratory-confirmed SARS-CoV-2-infected cases, at least in the early stages of the COVID-19 pandemic (2., 3., 4.). In a report of 72,314 laboratory-confirmed or suspected (based on history of exposure), symptomatic or asymptomatic SARS-CoV-2-infected cases by the Chinese Center for Disease Control and Prevention, children <19 years of age accounted for 2% of the total number of cases; in this study there was no difference in the rate of infection among children of different ages (4). In England, between January 16 and May 3, 2020, children represented 1.1% of 129,704 SARS-CoV-2-infected cases (2). In Italy, by March 2020 children <18 years of age with SARS-CoV-2 infection composed only 1% of the total number of patients (3). However, in Ontario, from January 15, 2020–December 29, 2020, 5.1% of the total confirmed COVID-19 cases were reported in children; in particular, the rate of infection among children was dramatically lower (60.4 per 100,000 population) than adults (298.8 per 100,000 population) (11). In this latter study, rates of illness were highest among children 15–19 year of age (109.6 per 100,000 population) compared to younger pediatric age groups (11).

Since these initial stages of the COVID-19 pandemic, the number of infected children has increased significantly. This is possibly since the criteria for testing for SARS-CoV-2 have changed as exposure risks, COVID-19 associated symptoms, laboratory testing capacity and priority populations have evolved over the course of the pandemic. In the United States, children <18 years of age account for approximately 13.3% of laboratory-confirmed SARS-CoV-2 cases (12). Time trends in reported incidence for children and adolescents aged 0–17 years tracked consistently with trends observed among adults. WHO data suggests that children <18 years represent approximately 8.5% of reported cases, usually with mild disease (13).

In terms of age groups, among >1.2 million children <18 years of age with SARS-CoV-2 infection in the United States between March and December 2020, children were distributed as follows (14):

Preschool (age 0 through 4 years)–7.4%

Elementary school (age 5 through 10 years)–10.9%

Middle school (age 11 through 13 years)–7.9%

High school (age 14 through 17 years)–16.3%

Based on serology studies, the reported number of laboratory-confirmed cases of SARS-CoV-2 infection in children is likely underestimated given the high proportion of mild and asymptomatic cases in which testing may not be performed (15,16). Most but not all studies show slightly more boys than girls being affected in the COVID-19 pandemic (6,17,18); however no significant sex difference has been observed.

Clinical Manifestations

Most children who become infected with the SARS-CoV-2 virus have either no, or mild symptoms. Depending on the study design, studies report the rate of asymptomatic children ranging from 16–35% (17,19,20). It is important to note that this is likely an underestimation of the true prevalence of asymptomatic SARS-CoV-2 infection, as children without symptoms seek testing much less frequently than symptomatic children (10). Indeed, serological studies demonstrate that half of children tested positive for SARS-CoV-2 reported no symptoms (15,16). Children and adolescents with COVID-19 may develop a wide spectrum of clinical manifestations which makes the empiric diagnosis of COVID-19 in children challenging (21).

In the case series we reviewed, fever was the most common sign at presentation, followed by cough, rhinorrhea, and sore throat (17., 18., 19.,22,23) (Supplementary Table 1). Other common symptoms were headache (16,17,22,24), diarrhea (3,17,20,24), vomiting (3,17,20), fatigue (20,22,24,25), myalgia (16,24,25), tachypnea (18,20), tachycardia (20), and rash (25).

Anosmia/ageusia is not frequent in children (24,26) but it is the strongest predictor of a positive SARS-CoV-2 test in both children and adults (19). Among symptomatic children, altered smell or taste, nausea or vomiting, and headache were more strongly associated with SARS-CoV-2 than other symptoms (19). However, cough, nasal congestion, sore throat, and fever are non-specific symptoms, since they are frequently encountered in children with COVID-19 as well as with other infectious diseases (2,19) In terms of clinical syndromes, children present as acute respiratory infection, influenza-like illness, isolated fever, gastroenteritis or vomiting and asthma exacerbation (24,27).

The proportion of severe and critical cases is lower in children than in adults. Dong et al found that the proportion of severe and critical cases was 10.6, 7.3, 4.2, 4.1, and 3% for the age groups <1 years, 1–5 years, 6–10 years, 11–15 years, and >15 years, respectively (6). Many studies suggest that children with certain underlying medical conditions such as chronic respiratory illness including moderate-to-severe asthma, obesity, diabetes, sickle cell disease or cancer and infants (age <1 year) might be at increased risk for severe illness from SARS-CoV-2 infection (28). Other studies found that infants were not at increased risk of severe disease (23) and had a good outcome without specific treatments (29). Of the children who have developed severe illness from COVID-19, most have had underlying medical conditions (30,31).

Children with severe COVID-19 may develop neurologic manifestations (up to 22% among 1695 hospitalized children and adolescents) (32), and occasionally acute disseminated encephalomyelitis (33), acute transverse myelitis (8), respiratory failure (31), myocarditis (34), shock (31), ocular symptoms (35,36) acute renal failure (37), and multi-organ system failure (31). In the large series of 1695 hospitalized children and adolescents with COVID-19, neurologic involvement was significantly more frequent among patients with underlying neurologic disorders (32). Some children with COVID-19 have developed other serious problems like intussusception or diabetic ketoacidosis (38,39). Children infected with SARS-CoV-2 are also at risk for developing Multisystem Inflammatory Syndrome in Children (MIS-C) a rare but serious condition associated with COVID-19 that has been reported in children (40,41). Among 440 cases, main findings include gastrointestinal symptoms, dermatologic/mucocutaneous symptoms, cardiac dysfunction, shock, and elevated markers (C-reactive protein, inteleukin-6, and fibrinogen levels) (42). MIS-C may begin weeks after a child is infected with SARS-CoV-2. The child may have been infected from an asymptomatic contact and, in some cases, the child and their caregivers may not even know they have been infected (40). A study of 186 cases from the United States, found that a minority of children had been symptomatic prior to the onset of MIS-C, and the median interval from COVID-19 symptoms onset to MIS-C was 25 d (41).

The United States Centers for Disease Control and Prevention (CDC) issued a Health Advisory (43) that outlines the following case definition for MIS-C:

An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological); and

no alternative plausible diagnoses; and

positive for current or recent SARS-CoV-2 (COVID-19) infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the onset of symptoms.

Most children with MIS-C with severe cardiac manifestations experienced clinical recovery within 30 d. The case fatality rate (CFR) in large cohorts was 0 (44), 1.9 (45), and 2% (46). Obesity is a risk factor for MIS-C, present in a quarter of the 570 patients in the CDC report (46). Beyond MIS-C, we found no published evidence of cases of post-COVID syndrome in children (47).

The rate of hospitalization among children varies depending on the criteria of hospital admission in different countries. In the United States the rate of hospitalization of children is low compared to that of adults (6), but it is increasing. The cumulative COVID-19–associated hospitalization rate among children aged <18 years was highest among children aged <2 years (32.7%); rates were substantially lower in children aged 2–4 years (8.7%) and 5–11 years (16.8%) but higher in ages 12–17 years (41.8%) (30). In Italy 57.7% of children with COVID-19 diagnosed by 28 centers in Italy (mostly hospitals) were hospitalized (18). In Greece 26.1% of the children diagnosed during the first epidemic wave were hospitalized; in this series being <5 years old predicted hospitalization (24).

In the cases series we reviewed few children required intensive care unit (ICU) admission. In particular, we found the following rates of ICU admission: 0 (25,48), 8 (17), 0.5 (24), 12 (18), 9.7 (27), and 18% (23). Risk factors for ICU admission include age <1 month, male sex, pre-existing medical condition, presence of lower respiratory tract infection, and signs and symptoms in presentation. Obesity and high mean peak inflammatory markers (ferritin, C-reactive protein, procalcitonin, D-dimer and IL-6) were significantly associated factors associated with mechanical ventilation (23). In the United States about 1 in 3 children hospitalized with COVID-19 were admitted to the ICU, similar to the rate among adults (30).

In terms of outcome, most children recover and there is no evidence of excess childhood mortality. In the studies we reviewed, CFR in children with COVID-19 was 0 (18,24,27,48), <0.3 (2), 0.69 (17), 0.58% and only one study found a CFR 2% (23) but in this latter study only symptomatic hospitalized children were included.

We should note however, that the full spectrum of consequences of the COVID-19 pandemic remains largely unknown. A model-based study has shown that the 1918 pandemic influenza virus produced different age-related immune responses against influenza A/(H1N1) pdm09 virus of 2009, with highest titers in the birth cohort born in 1911–1926, followed by the youngest born in 1987–1992 (49). The role of the ongoing COVID-19 pandemic on immune responses of different future birth cohorts remains to be elucidated (49). Similarly, to long-term sequelae of the 1918 influenza pandemic, it is possible that the COVID-19 pandemic will also have long-term consequences on the cohort that was in utero during the pandemic, either because of maternal infection or because of the stress of the pandemic per se (50). Finally, previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes (51). As we understand more about the immune response to SARS-CoV-2 there is the hypothesis that the early-life adversity-induced pro-inflammatory phenotype may play a role in determining the severity of COVID-19, rendering people vulnerable to COVID-19 many years later (51). Further research is needed to understand the underlying mechanisms.

Why Children have Milder SARS-CoV-2 Infection?

There are multiple explanations as to why children are infected less frequently and severely than adults. This may be related to the fact that children have a lower prevalence of co-morbidities such us hypertension, diabetes and chronic lung disease that have been associated with severe disease (52,53). Another explanation is the fact that children often experience coronaviruses in winter and have higher levels of antibodies against coronaviruses than adults. Antibodies directed against seasonal coronaviruses in children and young people might confer some protection, whereas waning of partly cross-reactive seasonal coronavirus antibodies in older people might place them at higher risk for antibody-dependent enhancement (54).

Some studies have raised controversial speculations regarding angiotensin-converting enzyme-2 (ACE2) receptors that have been proven to bind to SARS-CoV-2 spike protein and promote entry of the virus into human cells (55). It is speculated that children were less sensitive to COVID-19 because the maturity and function (eg, binding ability) of ACE2 in children may be lower than in adults (56). Bunyavanich et al identified a lower ACE2 expression in the nasal epithelium and suggested that it could be related to lower acquisition of SARS-CoV-2 infection in children (57). However, in the lower respiratory tract, it appears that decreased ACE2 expression could signify a higher risk of developing severe acute respiratory distress syndrome and lung injury. ACE2 catalyzes angiotensin II conversion to angiotensin 1–7, which can suppress inflammation, counteracts vasoconstriction and fibrosis by binding to the MAS receptor (58, 59). In animal studies it has been found that ACE2 plays a protective role from severe lung injury (60). Chen et al suggested an inverse relationship between ACE-2 expression and COVID-19 severity (59). Ιn particular, they found a significantly higher ACE2 expression level in Asian females and young people. ACE2 expression decreases with age and is lowest in people with diabetes (59). Further studies are needed to understand the distribution of ACE2 in cells in different tissues across human individuals.

Another explanation for the less severe symptoms in children is that children are mainly infected by the adult members of their families. So children are infected with a second or a third generation of the virus, which may have decreased pathogenicity (61). Furthermore, children have a stronger innate immune system and may respond to pathogens differently from adults. In healthy children, lymphocytes, especially NK cells, are constitutionally in greater amount than healthy adults (62). Lymphocyte count is very high in the first months of life and decreases in later childhood and in adolescence. Both frequent viral infections and live vaccines in children could induce an innate immune system enhanced state of activation, which would result in more effective defense against different pathogens (63,64). Finally, simultaneous presence of other viruses in the respiratory mucosa of children, may compete with SARS-CoV-2 (65).

However, children generally have a lower risk of cumulative exposures to SARS-CoV-2 and a lower likelihood of being tested compared with adults (40). For these reasons, it is difficult to determine how much of an observed difference in detected SARS-CoV-2 infection rates between children and adults may be attributed too biological or to epidemiological differences.

Transmission of SARS-CoV-2

Studies indicate that children are not the major vector of SARS-CoV-2 transmission in the community with most pediatric cases described in family clusters. The prevalent direction of virus transmission is adult-to-child rather than child-to-adult (24,66). In particular, only in 8% of households did a child develop symptoms before any other household member (25). In family clusters, the most common source of infection was a parent, considered the index case in 56% of cases, while in only 4% of cases the most probable index case was a sibling (17). Lastly, new SARS-CoV-2 variants emerged the past months, with higher (up to 90%) reproduction number and an increased impact on morbidity and deaths, based on model projections, compared with preexisting variants (67). The role of children in the transmission dynamics of these variants must be elucidated (67).

The Role of Schools

Transmission of SARS-CoV-2 has been reported to occur within educational settings. To reduce virus transmission, many countries implemented school closure at the national level. However, epidemiological investigation has revealed that SARS-CoV-2 transmission in schools concerns only a minority of COVID-19 cases in most countries, especially when infection control measures are employed. In Sweden, schools and preschools remained open, and a low incidence of severe COVID-19 among children was reported during the pandemic (68). A prospective cohort study in Australia employing case-contact testing showed that children and teachers did not contribute significantly to COVID-19 transmission when attending educational settings (69). Similarly, in Ireland, studies on pediatric cases of COVID-19 attending school identified no cases of onward transmission to other children or adults within the school, neither in primary nor in secondary school settings (70). In England, when schools re-opened after the first national lockdown, systematic national surveillance detected a low general risk of SARS-CoV-2 infection among staff and students in educational settings (71). In Germany after implementation of infection control measures for the prevention of SARS-CoV-2 transmission in schools and childcare facilities, child-to-child transmission was rare (72). In northern Italy, within-school transmission occurred in high schools, but no secondary cases were found in pre-school children, apart from one case in a primary school, and no secondary cases were detected among teachers (73). Another cross-sectional and prospective cohort study in Italy does not support the notion that school opening was a driving force of the second wave of SARS-CoV-2 epidemic in Italy (74). In Israel, schools fully reopened on May 17, 2020. Ten days later, there was a major outbreak of COVID-19 in a high school (75). The first case was registered on May 26, 2020, and the second on May 27, 2020, but there was no epidemiological link between the two. Testing of the complete school community revealed an attack rate of 13.2% among students and 16.6% among staff (75). A systemic review of 16 articles, including a modeling study, on school closures and other school social distancing practices during coronavirus outbreaks including COVID-19, revealed that school closures would prevent very few deaths, much less than other social distancing interventions (76). Moreover, transmission spread within schools can be drastically reduced with strict implementation of mitigating measures (71). These include frequent cleaning of contact surfaces, regular and interim ventilation of rooms, hand hygiene and use of a face mask inside and outside the classroom. Keeping physical distance among children is also recommended, as well as temporary exclusion of sick children (71). Indeed, a study of upper respiratory viral loads in children with SARS-CoV-2 infection found that asymptomatic children had significantly higher cycle threshold values than symptomatic children, while viral loads were 3–4 logs lower in the former compared to the latter (p-value <0.001); these findings were consistent across all institutions and by gender, ethnicity, and race (77). Moreover, a recent study justifies testing of quarantined contact traced students for SARS-CoV-2 infection on or after 9 d from exposure (78).

Closure of schools has a severely negative impact on children's and adolescents’ physical condition (79), their social interactions and well-being (80), and is associated with psychological problems (81), risk of obesity (82), and screen addiction (83). Open schools offer protection from situations of domestic abuse (84) and are important for maintaining and improving learning performance, especially in low-income settings. These data support the well-established belief that perils of school closures are not outweighed by potential benefits. In general, evidence from various studies and the fact that incidence among young children is significantly lower suggest that the risk of SARS-CoV-2 transmission among children associated with reopening childcare centers and elementary schools might be lower than that for high schools and universities (14,73). CDC therefore recommends that K-12 schools be the last to close after all other mitigation measures have been employed and the first to open when that can be done safely (85).

Vaccination

The past months COVID-19 vaccines trials are ongoing in children. Preliminary results show very good efficacy and tolerability (86). The US CDC and other public health authorities recommend persons 12 years and older should get vaccinated with the Pfizer-BioNTech COVID-19 vaccine (87). An age-structured disease transmission model found that in a base-case scenario with an effective reproduction number Re = 1.2 and in the absence of vaccine availability for children, rapid identification of silent infections in this age group is required to mitigate disease burden (88). Vaccination of adults is unlikely to contain COVID-19 outbreaks soon without measures to interrupt transmission chains from silent infections (88). Vaccination of children and adolescents is recommended to protect them against COVID-19, but mostly to contribute to the achievement of herd immunity across all age groups (89).

Competing Interest

Theackre is no conflict of interest to declare.