COVID-19 in Early Life: Infants and Children Are Affected Too

Abstract

Compared with adults, children are less likely infected with SARS-CoV-2 and are often asymptomatic when infected. However, infection in children can lead to severe disease. The pandemic affects the lives of all children, especially those with lower socioeconomic status. This review highlights the physiological impacts of COVID-19 in early life.

Introduction

Coronavirus disease 2019 (COVID-19) has had a catastrophic impact in the world, with over 155 million people infected, and over 4.10 million confirmed deaths (World Health Organization) as of July 19, 2021 (https://coronavirus.jhu.edu/map.html). It is often more severe in people who are over 60 yr old and those with comorbidities affecting their pulmonary, cardiovascular, endocrine, and immune systems. Based on Centers for Disease Control data, among all infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the US, 2% occur in children 0–4 yr of age, and 9.7% occur in children 5–17 yr of age (https://covid.cdc.gov/covid-data-tracker/#demographics), both underrepresented compared with percentages of the US population in the respective age groups. Only 0.1% of COVID-19 associated deaths occurred in children <18 yr of age. Similar numbers are reported worldwide. In Korea, in a case series of children with confirmed detection of SARS-CoV-2 RNA, only 9% of were diagnosed based on symptom onset, and 22% were asymptomatic throughout their course of infection (1). The American Academy of Pediatrics has been tracking COVID-19 cases in children and concludes that although severe illness is rare among children, it is imperative to continue to monitor the long-term physical, emotional, and mental health of children, including those who were infected and those secondarily affected by the societal changes brought on by the pandemic (https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/).

Complex Biological Basis for Lower Infection Rates and Disease Severity in Children Compared With Adults

Contributors to differences between pediatric and adult COVID-19 likely involve distinctions between developing versus developed tissues, as well as expression of the host machinery that the virus uses for cellular entry. In addition to tissue-level differences, immune system differences are likely a key factor.

To study these differences in immunity, Pierce et al. (2) compared cytokine, humoral and cellular immune responses in COVID-19 patients younger than 24 yr of age (mean 13.34 yr) to those older than 24 yr of age (mean 61.05 yr). The data confirm that the younger patients had a less severe pulmonary disease burden including decreased need for mechanical ventilation and lower mortality rates. The investigators found that the serum level of interleukin-17A (IL-17A) and interferon-gamma (IFN-γ) were inversely correlated with age. These cytokines have been shown to serve a protective role in pulmonary infections (3, 4). Adults mounted a more robust T-cell response, had higher neutralizing antibody titers, and antibody-dependent cellular phagocytosis activity, contributing to the increased risk of acute respiratory distress syndrome.

Although children overall are at a lower risk of severe disease, children of differing ages could present distinct symptoms, leading investigators to examine clinical and laboratory characteristics of children ages 0–1, 1–5, and 5–15. In one study (5), infants less than a year of age were more susceptible to pneumonia from SARS-CoV-2 (88.8%) as compared with older children (46.9%). Peripheral blood samples from the three age cohorts showed decreased white blood cells, lymphocytes, natural killer cells but increased neutrophils in infants (0–1 yr) compared with the older children, probably reflecting the immaturity of their immune systems. This study defined “severe” disease as an elevated respiratory rate, hypoxia and hypoxemia, and worsening chest X-ray. Only one patient was admitted to the intensive care unit (ICU) out of the cohort of 173 patients. In contrast, a more recent meta-analysis using electronic databases in the US, examined 20,714 pediatric patients with COVID-19 and found that 31.1% of hospitalized pediatric patients experienced severe disease, which they defined as requiring care in an intensive care or step-down unit, requiring invasive mechanical ventilation or resulting in death (6). Their analysis found that there was an increased association of severe COVID-19 in younger children (ages 2–11) versus older children (ages 12–18), although they acknowledged being unable to evaluate associations among infants younger than 12 mo. Severe COVID-19 was independently associated with existing chronic conditions and the male sex in the meta-analysis (6).

Cutting-edge single cell RNA sequencing (scRNAseq) data suggest that a lower expression level of host factors hijacked by the virus for cellular entry may contribute to lower infection in children (7, 8). It is well established that the angiotensin-converting enzyme 2 (ACE2) receptor is a primary receptor for SARS-CoV-2 (9, 10). Furthermore, TMPRSS2 is key protease that cleaves the Spike protein on the surface of SARS-CoV-2, a requisite step for viral entry (11). scRNAseq data from normal human lungs from donors at 30 wk of gestation and 3 yr and 30 yr of age showed that both ACE2 gene and TMPRSS2 gene are expressed primarily in lung epithelial cells, which constitute the first line of defense against the SARS-CoV-2 infection. In these cells, the expression of both genes was found at a lower level in pediatric lungs compared with adult lungs (7). The same donor lungs were also used to generate single nucleus assay for transposase-associated chromatin using sequencing (snATACseq) data, a powerful assay for high-resolution chromatin accessibility that underlines gene regulatory control. snATACseq data revealed candidate cis-regulatory elements with increased activity correlated to age, that may underlie the increased expression of the host entry genes (7). The age-dynamic expression was also corroborated by the aforementioned study of children ages 0–1, 1–5, and 5–15 (5). Correlating with the more severe disease in the youngest group, there was a higher proportion of ACE2+ SOX9+ lung progenitor cells, which were rarer in older children (5). These findings together reveal molecular differences that may contribute to age-associated differences in infection rate and disease severity.

Transmission in Children

SARS CoV-2 is a highly infectious virus (12) and is transmitted either as respiratory droplets, aerosol particles or contact with respiratory secretions and saliva (13). Transmission to children can occur in a variety of ways (FIGURE 1). Vertical transmission from the mother to the fetus has been raised as a possible path since the placenta expresses the ACE2 receptor. While an earlier systematic case review found no evidence of vertical transmission (14), there have been multiple confirmed neonatal cases of COVID-19 with pneumonia and positive nasopharyngeal swabs for SARS-CoV-2 in both infants and mothers (15–17). A recent large review of the current literature revealed that there is likely vertical transmission in the third trimester (18). This meta-analysis revealed that 3.2% of neonates born to mothers with COVID-19 had positive nasopharyngeal tests after birth (19). The virus was also detected in the cord blood and placenta and fecal or rectal swabs of neonates. Among cases where serology was tested, 3.7% was confirmed positive based on the presence of immunoglobulin M. These results have come mostly from case reports, and there is still not consensus over whether SARS-CoV-2 is vertically transmitted via the placenta to the fetus.

FIGURE 1.

Modes of transmission to babies, infants, and children Schematic showing how SARS-CoV-2 is transmitted from adults to infants and children. Vertical transmission in pregnancy via the placenta is still controversial although recent meta-analyses support this. Transmission via droplets and direct contact from adults is well documented, and children and infants also transmit to other children and adults, albeit at a lesser degree. Finally, there is no current evidence showing that SARS-CoV-2 can be transmitted via breastfeeding.

Breast milk samples have also been evaluated as another potential source of mother-to-infant transfer of SARS-CoV-2. Milk samples from mothers with COVID-19 did not show replication-competent virus (20). A systematic review of 37 studies confirmed that there was no evidence of SARS-CoV-2 transmission through the breastmilk (21). Therefore, the World Health Organization (WHO) recommends that mothers with COVID-19 continue to breastfeed, although these recommendations have not been widely adopted (22).

A major source of transmission to children comes from other children. Children are more likely than adults to have upper respiratory tract involvement which may prolong respiratory shedding (23). This, along with the lack of symptomatology may allow them to spread the virus to close contacts unknowingly (24, 25). The age of a child also affects transmission. In a study of contact tracing data in South Korea from January to March 2020, the highest infection rates were found to occur in children 10–19 yr (18.6%), while those younger than 10 yr had a lower rate of transmission (5.3%) (26). Rates of infection are also higher among racial and/or ethnic minority groups of children (27).

Schools and childcare facilities can also play a role in transmission albeit shown to be less of a factor than community spread (28, 29). Multiple worldwide studies indicated that most school-related outbreaks can be traced back to an adult staff member (30–35). In an Australian study, the secondary attack rate (SAR) from child to child was 0.3%, from child to staff SAR was 1.0% and the staff-to-staff SAR was 4.4% (34). One large outbreak in a school in Israel did involve child-to-child transmission but was blamed in part on crowded classrooms and lack of physical distancing and mask usage (36).

Clinical Symptoms of COVID-19 in Children

Although COVID-19 infection is most commonly asymptomatic or mild in children, severe disease can occur as well. The most common symptoms of COVID-19 in children are cough and fever (37). Older children are also more likely to present with symptoms such as vomiting, abdominal pain, headache, sore throat, and loss of taste and smell (38). In a retrospective case series studying clinical manifestations of children hospitalized with COVID-19, obesity was significantly associated with severe disease (defined as hospitalization requiring mechanical ventilation), while infancy and immunocompromised status were not, although the study was limited by a small sample size (39). In a systematic review of 7,780 pediatric patients (40), mortality was low at 0.09% but severe disease was seen mostly in children with underlying conditions (35.6%) and immunosuppression (30.5%). In a case series from China of 2135 pediatric patients with COVID-19, 4% of children were asymptomatic, 51% had mild illness, 39% had moderate illness, and 6% had severe illness (41). Most of the severe and critical cases occurred in children less than a year (10.6%) compared with older children, but among all infants, the most common presentation was mild (54.2%). ICU admission data was not collected. Compared with the US pediatric COVID-19 cohort (6), there were no sex differences in those with severe COVID-19 in this study of Chinese cases. Thus the impact of severe COVID-19 disease in the pediatric population differs internationally.

Inflammatory Complications in Children With COVID-19

Although the first wave of epidemiological studies from China showed that children were spared the most severe COVID-19 symptoms, Multisystem Inflammatory Syndrome in Children (MIS-C) emerged from infected children, and it shared characteristics with Kawasaki Disease (42–47) including coronary aneurysms (48). Although definitions can differ from study to study, MIS-C presents in individuals <21 with fever, elevation in inflammatory markers along with severe multisystem organ involvement (49–51) (FIGURE 2). The most prevalent symptoms include fever, gastrointestinal complaints, rash, and conjunctivitis (52, 53). More severe symptoms such as shock and coagulopathy were also noted (54). Males and females were affected equally. Unlike Kawasaki disease, which preferentially affects Asian and Pacific Islander children, children affected by MIS-C were predominantly Hispanic and Black (44, 48, 51–53, 55) and were in the 5–14 age group (56). Current pathophysiological data indicate that SARS-CoV-2 infection triggers macrophage and T cell activation, which leads to cytokine release including IL-6, IL-10 and activation of interferon signaling (42). Gruber et al. (57) characterized the plasma cytokine profile differences between children with COVID-triggered MIS-C and those with COVID-19 without MIS-C. Principle component analysis showed unique chemokines (CXCL5, CXCL11, CXCL1, and CXCL6) and cytokines (IL-17A, CD40, and IL-6) distinguishing MIS-C patients (57). There was also signature B cell activation leading to antibody production and immune dysregulation (56). MIS-C plasma showed elevated immunoglobulin G (IgG) with low levels of IgM, which was similar to regular convalescent plasma. However, IgA levels far exceeded those seen in convalescent plasma (57). The timing of symptom onset for MIS-C is ∼4–6 wk after COVID-19 infection (38, 55). While only 52% of children had a positive RT-PCR for SARS-COV-2, high viral IgG antibody titers were found in 71% of children (50). Although pediatric mortality rates were low, children with MIS-C were five times more likely than children with COVID-19, but not MIS-C, to be admitted to the ICU (38). The most severe cases were generally associated with comorbidities. Treatment with anti-IL-6R and intravenous immunoglobulin (IVIG) rapidly normalized proinflammatory markers and resulted in good outcomes in a small cohort of patients, but these are not standard therapy (58). In another small cohort of 21 children, who met WHO criteria for MIS-C, all received corticosteroids, while 33% received IVIG (59).

FIGURE 2.

Signs of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection The figure summarizes the signs of MIS-C including neurological (meningismus), respiratory (hypoxemia), cardiovascular (myocarditis, coronary aneurysms), and gastrointestinal (vomiting and diarrhea).

Comorbidities Impacting COVID-19 Severity in Children

Children at risk of severe disease include those with various comorbidities including obesity (39, 60), congenital heart disease, pulmonary hypoplasia/anomaly, anemia, malnutrition, and immune deficiency (61). A large meta-analysis confirmed that childhood obesity was associated with worse prognosis of COVID-19 infection but could not verify any impact of other comorbidities (62). The authors postulated that the high visceral adiposity induced higher levels of inflammatory cytokines including IL-6 and C-reactive protein (63), which had been correlated with COVID-19 severity. Proinflammatory populations of macrophages were also observed in obese individuals (64), which may contribute to the dysregulated immune response to infection. Due to the lack of robust data studying the effects of comorbidities in children, there are now large, international databases and registries established to prospectively collect data. Recent articles have reported a link between gastrointestinal disease (65) and sickle-cell disease (66, 67) to COVID-19 severity in children.

Early Life Adversity Effects

There is a well-established correlation between social adversity and reduced host resistance to infection and disease (68). As the COVID-19 pandemic progressed, it became clear that many inequalities in susceptibility and severity of the disease were present. Multinational data confirmed that lower socioeconomic status was linked to greater risk of COVID-19 (69). The Barker theory, i.e., the Developmental Origins of Health and Disease, states that environmental influences early in life may determine susceptibility to disease (70–72). In practice, the Barker theory is applied in a three-hit model which includes 1) genetic predisposition, 2) early life environment, and 3) later life environment (73). In many diseases that likely includes COVID-19, a main mediator of the adverse effects is the immune system, through chronic low-grade inflammation and immune senescence. A large cohort study (EpiPath) investigating early life adversity observed an increase in activated and senescent proinflammatory T cells, although B cells were not altered (74). Early life adversity is associated with psychological stress, infection, changes in the microbiome and nutrition and pollution, which are all encompassed in social economic status (75). Therefore, a dysregulated immune response to infection may underlie the observation that children raised in a lower socioeconomic status have a higher rate of infection.

Although immune system dysregulation is one contributor that may predispose children to early life adverse events, nonphysiological adverse events, such as environmental pollution, lack of attention from working parents, increased amount of individuals living in the home, and diet, can also underlie increasing severity of COVID-19 in children.

COVID in Early Child Growth and Development

COVID-19 not only impacts children physically, school closures, public places shutdowns and social distancing have become risk factors that negatively impact child growth and development. As discussed previously, environmental influences can affect learning capacities, adaptive behaviors, and lifelong physical and mental health (76). Thus it is imperative to understand and identify adverse childhood experiences (ACEs). ACEs are traumatic or stressful events, including pandemics. After schools were closed in Hubei province in China, investigators interviewed over 1,700 students to assess their mental health. Twenty two percent of students reported depressive symptoms and 18.9% reported anxiety symptoms (77). Prolonged depression and anxiety may lead to negative impacts on the cardiovascular and neurological health of the child (78). Unfortunately, there has also been an increased rate of youth suicide ideation and attempts, which appeared to correspond to COVID-19 related stressors (79). On the positive side, the plasticity in a child’s physical and mental development, and the support the child receives from adults including security and affection can facilitate a return to normalcy (80).

Postacute Sequelae of SARS-CoV-2 Infection (PASC)

Postviral syndromes or complications that occur after infection with SARS-CoV-2, also called “long-haul COVID,” can also affect children (81). Although most children are asymptomatic or have mild symptoms of COVID-19, a small percentage continue to have symptoms weeks to months after initial infection. These include fatigue, joint pain and trouble breathing. It is thought to be due to dysregulation of the immune system and hyperactive inflammation resulting in tissue damage (82). When evaluated biochemically, children with postacute sequelae of SARS-CoV-2 infection (PASC) had elevated plasmablasts and IgD-CD27+ memory B cells and elevated IL-6 and IL-1 beta cytokines. National agencies such as National Institutes of Health have directed attention to studying the definition, cause and treatment of PASC, including in pediatric cohorts.

Future Directions

COVID-19 is a novel disease and there has been a flood of data published about the biological and psychological effects it has on children. Some of the findings are contradictory to each other, which underscore the complexity of COVID-19 that may be context dependent. More importantly, the contradictions put emphasis on rigor in our investigation. Despite intense research activity, there are notable areas with open questions. A compelling area of future study is to examine the clinical outcomes of women who are SARS-CoV-2 positive during their first and second trimester of pregnancy, since most of the current literature focuses on the third trimester. The effects of COVID-infection induced maternal stress on prematurity should be studied with large international sample sizes. Also, longitudinal studies should be done to examine development (i.e., physical and neurological) of infants born to SARS-CoV-2-positive mothers or are infected after birth. More comprehensive studies based on larger sample sizes are needed to better characterize the laboratory and clinical profiles of mild versus severe pediatric COVID-19 and to help identify effective interventions to ameliorate long-term impacts. Within this realm, emphasis needs to be paid to understanding how lower socioeconomic status factors impact children from minority racial and ethnic groups. Comorbidities are one aspect of increased risk of severe disease, but other factors such as nutrition, pollution and psychological stress can be minimized to provide all children with improved outcomes, not only in early life, but long-term as well.

While clinical research is important in understanding the effects of COVID-19, basic science is also imperative in defining the biology of SARS-CoV-2 infection, the relationship between infection and immunological response, and identify potential therapeutic targets. Large single cell RNAseq data sets on patients who died of COVID19 have helped to elucidate the changes in both the lung and immune cells (83, 84). Model systems such as immortalized cell lines and organoids have been useful in elucidating the biology in infection and possible therapeutics with monoclonal antibodies and various compounds in vitro (85–90). It is imperative to continue supporting basic science to understand the early mechanisms of viral infection and to develop novel therapeutics targeting both infectivity and the immune system to prevent severe infection, decrease the length of time of illness, and reduce the risk for PASC.