Pediatric COVID
Anna Martens
Lael Yonker
INTRODUCTION
During the early phases of the coronavirus disease 2019 (COVID-19) pandemic, hospitals were inundated with adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whereas children were reportedly spared from the virus. In retrospect, it seemed unlikely that a highly infectious respiratory virus inciting a global pandemic would spare children; however, at the time in early 2020, epidemiologic reports demonstrated disproportionately low numbers of infections in young age groups.1, 2 and 3 As time progressed, however, it became clear that children can become infected with and transmit the SARS-CoV-2; ultimately, COVID-19 became a leading infectious cause of hospitalizations4 and death in children during the peak of the pandemic.5,6 However, the impact of the pandemic on children became controversial and safety precautions to minimize infection of children were highly polarized. Although SARS-CoV-2, for the most part, causes milder illness with far fewer deaths in children as compared to adults, children nonetheless suffer from both the direct consequences of the virus, such as severe illness from acute infection and post-COVID illnesses (eg, multisystem inflammatory syndrome in children [MIS-C] or long-COVID), plus indirect consequences, including increased rates of new-onset diabetes or other medical complications, increased mental health illnesses, routine vaccination delays, loss of education, and food insecurity.
The early misconception that children were spared from COVID-19 was not unwarranted; hospitalizations and death rates of infected adults and elderly individuals surged when the pandemic hit, resulting in critical shortages of hospital staffing and intensive care unit (ICU) beds. Healthcare systems had to react, and pediatric medical teams were redeployed to provide care for adults. Simultaneously, as schools shut down and families quarantined, non-COVID-19 infections, such as influenza, essentially disappeared.7,8 As a result, the number of pediatric hospital admissions decreased by an estimated 45.4%. However, this decrease in pediatric volume was likely multifactorial, including not only decreased respiratory illnesses in the setting of social distancing but also delays in seeking medical care secondary to fear of COVID-19, lack of activity-related injuries, and deferment of elective surgeries.9 In order to expand adult capacity in hospitals, many states participated in consolidation of pediatric care through regionalization of pediatric patients from general hospitals to dedicated pediatric hospitals, opening up the pediatric beds in general hospitals to adults.10, 11 and 12 With this shift in care, pediatric ICUs and hospital beds were filled with adults, and pediatric providers were asked to care for parents and grandparents rather than children. This necessary reallocation of resources and extreme efforts to understand how adults were being impacted by COVID-19, along with a shortage of resources, limited personal protective equipment and lab supplies, resulted in delayed efforts to understand if and how children were impacted by COVID-19.
However, just 2 months into the pandemic, clusters of children began presenting with acute illness requiring ICU admission for a severe inflammatory condition with Kawasaki disease (KD)-like features, with high fevers, rash, and severe myocardial injury. The first cases were identified in Italy and the United Kingdom,13,14 then New York City,15 and soon began to be identified worldwide.16 Cases presented in clusters, always following COVID-19 surges, but with 1- to 2-month delays. Children presented acutely and critically ill with multiorgan dysfunction including cardiogenic shock, and it was identified that all children with this condition had a recent COVID-19 infection or exposure. The illness became most commonly referred to as MIS-C but has also been called
pediatric inflammatory multisystem syndrome temporarily associated with COVID-19 (PIMS-TS) or pediatric multisystem inflammatory syndrome (PMIS). Although rare, the development of this life-threatening illness made it apparent that children were not as protected from the virus as it was initially thought. Efforts shifted to better understand how children were affected by both acute COVID-19 and this postinfectious complication. Additionally, understanding the symptoms, infectivity, and patterns of transmission in children and adolescents became crucial for developing control measures for COVID-19 disease.
pediatric inflammatory multisystem syndrome temporarily associated with COVID-19 (PIMS-TS) or pediatric multisystem inflammatory syndrome (PMIS). Although rare, the development of this life-threatening illness made it apparent that children were not as protected from the virus as it was initially thought. Efforts shifted to better understand how children were affected by both acute COVID-19 and this postinfectious complication. Additionally, understanding the symptoms, infectivity, and patterns of transmission in children and adolescents became crucial for developing control measures for COVID-19 disease.
Because of the misconception that children were spared from COVID-19 and because of the redeployment not only of clinical staff but also of researchers and scientists to care for adults with COVID, research efforts primarily focused on adults infected with SARS-CoV-2. Fewer pediatric biorepositories were established; however, those that were established found success in paralleling adult enrollment strategies and protocols.17,18 Consortiums were developed to facilitate collaboration among research groups and ease for sharing samples with a wide range of researchers. The establishment of these biorepositories and consortiums allowed for a better understanding of how children are impacted by and contributed to the COVID-19 pandemic.
This chapter describes the advances made thus far in understanding acute SARS-CoV-2 infection in children, the postinfectious conditions seen in children (such as MIS-C and long-COVID), and SARS-CoV-2 targeted vaccination in children, highlighting lessons learned and questions yet unanswered in order to support further advances in the field.
ACUTE SARS-COV-2 INFECTION IN CHILDREN
Incidence and Prevalence in Kids
During the early phases of the SARS-CoV-2 pandemic, initial studies suggested that the incidence in children and adolescents was nominal compared to that of adults. However, this dichotomy was likely due to decreased testing frequency in children, lack of care seeking or access to testing in children, less exposure opportunities to contract the virus in children because of prevention measures, and that children were less susceptible because of differences in baseline immune function.
As the pandemic progressed, schools returned to in-person learning, and mask mandates were lifted, pediatric cases began to rise.19 COVID-19 cases among children then spiked dramatically in 2022 during the Omicron variant winter surge, at a time when most countries relaxed public health and social distancing measures, peaking at 1.15 million cases in children in 1 week. Subsequently, cases decreased dramatically after the Omicron peak19; however, the number of reported positive cases is felt to be a marked underestimation given the number of asymptomatic cases, undiagnosed cases, and unreported positive home tests. As of December 2022, over 15 million children are documented as having tested positive for COVID-19 since the onset of the pandemic, representing 18.5% of total cumulative cases. Despite most children not suffering the same severity of illness following SARS-CoV-2 infection as adults, roughly 170,000 children have been hospitalized for COVID-19 (Centers for Disease Control and Prevention [CDC] Data Tracker) and pediatric deaths from SARS-CoV-2 far exceed pediatric deaths from influenza and other viruses.5,20
Seroprevalence (the proportion of the population with SARS-CoV-2 antibodies) is an alternative technique to improve the understanding of population-level incidence of COVID-19, and multiple studies have now demonstrated that even early in the pandemic, children may have had similar incidence rates of SARS-CoV-2 infection compared to adults, but a larger proportion of infections among children were asymptomatic or mild.21, 22, 23, 24, 25, 26 and 27 By February 2022, 75% of children and adolescents (0-17 years old) in the United States were estimated to have been seropositive for SARS-CoV-2, with one-third of these seroconversions having occurred between December 2021 and February 2022, underscoring the high infection rate from the Omicron variant among children.24 Fortunately, with the availability of effective vaccines for people 6 months or older, we began to see decreases in COVID-19 cases, hospitalizations, and deaths in children.28,29
Racial Disparities
As with adults, COVID-19 has disproportionately affected children of racial and ethnic minority groups. In the early phases of the pandemic, when compared with White children, those of Black, Hispanic, and Asian race/ethnicity had lower rates of testing; however, when tested, they were significantly more likely to have positive test results.30, 31, 32 and 33 Additionally, Hispanic or Latino and
non-Hispanic Black children had higher cumulative rates of COVID-19-associated hospitalization when compared to non-Hispanic White children.34 These disparities among most racial and ethnic minority groups compared with White persons were more substantial early in the pandemic and then decreased over time. These racial and ethnic disparities might reflect differential ability to participate in early mitigation measures, such as stay at home orders, because racial and ethnic minority groups are disproportionately represented in essential work settings and have a higher likelihood of living in multigenerational household, increasing exposures to the virus.35
non-Hispanic Black children had higher cumulative rates of COVID-19-associated hospitalization when compared to non-Hispanic White children.34 These disparities among most racial and ethnic minority groups compared with White persons were more substantial early in the pandemic and then decreased over time. These racial and ethnic disparities might reflect differential ability to participate in early mitigation measures, such as stay at home orders, because racial and ethnic minority groups are disproportionately represented in essential work settings and have a higher likelihood of living in multigenerational household, increasing exposures to the virus.35
Symptomatology
Compared to adults, children and adolescents are more likely to be asymptomatic or have mild symptoms. Most common symptoms include fever, headache, cough, rhinorrhea, vomiting, and diarrhea (Figure 11.1).26,27,36, 37 and 38 Younger children may have decreased feeding and can be at greater risk for dehydration. Respiratory distress can occur, such as in COVID-19 bronchiolitis or COVID-19 pneumonia, which may prompt hospitalization for respiratory support or supplemental oxygen.39,40 Additionally, apnea can occur in infants. Only a small proportion of infected children become severely or critically ill with progression to acute respiratory distress syndrome with or without multiple organ dysfunction. Complications resulting from acute COVID-19 infection can also occur in children with increased rates of pulmonary embolism and myocarditis.38,41
 FIGURE 11.1 Pediatric COVID-19 overview. (1) Decreased expression of ACE2 receptors in children’s respiratory epithelium would limit viral fusion and replication. (2) Children have higher mucosal colonization by viruses and bacteria, causing interactions and competition with other viruses, limiting the colonization and growth of SARS-CoV-2. (3) Airway epithelium in children has increased amounts of immune cells and are primed for virus sensing, allowing for early recognition and clearance of the virus. (4) Children infected with SARS-CoV-2 generate a comparable humoral response to adults with mild COVID-19 but are less likely to develop the hyperinflammatory serologic response that may protect. Children also more rapidly produce protective anti-spike neutralizing antibodies (nAbs) after SARS-CoV-2 exposure, which assist in blocking invasion of virus into the cell. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. (Created with BioRender.com) |
Risk Factors for Severe COVID-19
It is difficult to draw conclusions on risk factors for severe COVID-19 in children as available studies are context specific and dependent on timing within the pandemic. Differences in the understanding of the virus at the time of study completion, testing capability, altering variants, and population characteristics likely impact these numbers. However, current research suggests that young age (<1 year old), male sex, and certain preexisting conditions (obesity, chronic pulmonary disease, congenital heart disease, and neurologic disease) may increase a child’s risk for developing severe COVID-19 (Figure 11.1).25,27,42,43 Higher hospitalization rates in less than 60-day-old age groups compared to other ages may be related to the need to rule out serious bacterial infections in this vulnerable age group and less reflective of severity of disease.39,44, 45 and 46 Some studies demonstrate that Hispanic children and non-Hispanic Black children are also at an increased risk of severe COVID-19,34,47 although others have not found a statistically significant correlation between race/ethnicity and severity of symptoms.48 Childhood cancer is another risk factor that is associated with increased severity of COVID-19, but it is unclear if all children who are immunocompromised are at increased risk.49, 50, 51 and 52 Finally, children that are unvaccinated against COVID-19 have been noted to have higher rates of hospitalizations and are more likely to require ICU admission because of more severe COVID symptoms.53
Virology
Like adults, both symptomatic and asymptomatic children carry high quantities of live replicating SARS-CoV-2 virus and have detectable viral loads in nasal secretions.54,55 Age does not appear to be a predictor of viral infection dynamics; children of all ages can have high SARS-CoV-2 viral loads of replication-competent virus, including variants, with comparable dynamics to those seen in adults.17,55 The live virus is likely to clear within 5 days, corresponding with current CDC quarantine guidelines. Children carry variants reflective of those most prevalent in the community. As the pandemic progressed, waves of the pandemic, such as the Omicron surge, infected children with increasing rates. However, it is unlikely that this is reflective of the variants themselves and more likely reflective of trends in alterations of protective measures being taken by society at the time of the surge.55
Transmissibility
Although it was initially thought that children could not transmit the virus, it is now clear that children and adolescents can transmit SARS-CoV-2 infection at comparable rates to adults. At the onset of the pandemic, children were rarely identified as index cases in household or other clusters, as most cases in children resulted from household exposure with an adult as the index patient.56, 57, 58 and 59 This initial finding reflects strict physical distancing measures such as school and extracurricular activity closures, limiting the exposure of children to close contacts outside of their household. Still, there were lower
secondary attack rates among children with household exposures compared to adults.60 Since liberalization of social distancing measures and reopening of schools, camps, and sporting events, as well as the emergence of more transmissible variants, pediatric index cases have become more common, with secondary attack rates and child-induced household outbreaks comparable to rates in adults.37,61, 62, 63, 64, 65 and 66
secondary attack rates among children with household exposures compared to adults.60 Since liberalization of social distancing measures and reopening of schools, camps, and sporting events, as well as the emergence of more transmissible variants, pediatric index cases have become more common, with secondary attack rates and child-induced household outbreaks comparable to rates in adults.37,61, 62, 63, 64, 65 and 66
Transmission is dependent on multiple factors including disease severity, viral load, variants, duration and timing of exposure, and host factors such as baseline susceptibility and immune factors in the exposed individual.67 Asymptomatic children may be less likely to transmit the virus than symptomatic children; however, asymptomatic/presymptomatic children have been shown to have equally high levels of viral RNA early in the infection as compared to their symptomatic infected peers.17,68 Importantly, children display differences in respiratory dynamics as compared to adults, which impacts aerosol production and may affect their ability to transmit the virus. For example, young children have lower exhaled airspeed with less airway collapse. This could impact aerosol and droplet concentration and spread.69, 70, 71 and 72
Transmission in Schools
Once it became clear that children could both contract and transmit the virus, the reopening of schools was significantly delayed as it seemed inevitable that returning to the classroom would increase caseloads in children and family members. Ultimately, as schools began reopening after months- to year-long closures, measures were put into place to limit the transmission among students and teachers. This included hybrid models to minimize class size, daily fever and symptom screening, physical distancing, and daily COVID-19 testing. Studies assessing the effectiveness of these measures have allowed schools to adapt and refine their policies. For example, given the number of mild and symptomatic cases in children that do not present with a fever, temperature monitoring has been proven to be insufficient as a primary means of detection.73,74
Although transmission in schools can occur, population studies demonstrated that the reopening of schools was not associated with increased prevalence or incidence of overall COVID-19 infections compared to the general community. Within-school transmission of cases has been extremely limited, and in fact, the risk of contracting the virus is lower when exposed at school compared to at home. This is likely related to strict masking policies, distancing measures, and screening test.75, 76, 77, 78, 79, 80 and 81 Although most schools have forgone these safety precautions as time progressed, evidence suggests that the longer these safety precautions were in place following a COVID-19 surge, the fewer COVID-19 cases occurred,82 highlighting the compounding impact of these safety measures in schools over time.
Vertical Transmission and Breastfeeding
Although exceedingly rare, vertical transmission of the virus from a COVID-19-positive mother to the newborn is thought to be possible in a minority of cases of maternal COVID-19 infections in the third trimester. Evidence suggests that the transmission can occur either before or during delivery, though rare.83 Currently, there is no evidence of SARS-CoV-2 transmission through breast milk, and breastfeeding appears to be safe in mothers with COVID-19 if appropriate infection control measures are taken.84,85
Immunology
The SARS-CoV-2 virus is transmitted via respiratory droplets and aerosols from person to person. The nose is the first site of viral invasion into the body and it then travels to the respiratory epithelium of the lower airways and then to the alveoli. The virus’s spike (S) protein attaches to the angiotensin-converting enzyme 2 (ACE2) receptors of the respiratory epithelium, resulting in fusion of the membranes. Two proteases, transmembrane protease serine 2 (TMPRSS2) and cathepsin L (CTSL), are involved in this fusion process. Postmembrane fusion, the viral contents are released inside the epithelial cells and undergo RNA replication, transcription, and translation. New viral particles are synthesized and released into the extracellular space through exocytosis. At the same time, it also kicks off a cascade of events including a cytokine storm. The host’s immune syndrome subsequently responds through chemoattraction with neutrophils, CD4, and CD8 cells along with B-cell differentiation. The sequestration of inflammatory cells in the lung tissues results in CD8 cytotoxicity as well as lung injury. ACE2 is present in most organs, and activation of these receptors explains the extrapulmonary manifestations of COVID-19.17,86,87
Proposed Differences in the Pediatric Immune Response
A number of differences in children’s innate and adaptive immune systems have been proposed to explain the generally milder nature of COVID-19 infections in children (Figure 11.1).
Decreased expression of ACE2 receptors in children
Children have lower expression of ACE2 receptors in their nasal epithelium and lower airways than adults do, as the expression in the respiratory tract increases with age. A reduction in the viral receptor would limit fusion and replication of the virus.17,87, 88 and 89
Viral interference
Viral interference is a phenomenon where one virus interferes with the replication of a second virus. It is thought that infection of other common childhood viruses is associated with decreased expression of ACE2 in respiratory epithelial cells. Additionally, children have higher mucosal colonization by viruses and bacteria, causing interactions and competition with other viruses and therefore limiting the colonization and growth of SARS-CoV-2.17,87,90, 91 and 92
Heightened innate immunity
Given increased exposure to common childhood viruses, the airway immune cells of children are primed for virus sensing and response, allowing for a stronger early innate antiviral response to SARS-CoV-2 infection. Through RNA sequencing studies comparing the cellular composition of upper airways in adults and children, children were noted to have increased amounts of innate immune cells in their upper airways.92,93 Children have also been found to have increased proportions of activated neutrophils during the acute phase of SARS-CoV-2 infection,94 which may be a result of higher levels of viral pattern recognition receptors on their epithelial cells allowing for more efficient activation. Once a cell recognizes the virus, it has only a short time to produce interferons (IFNs—cytokines with antiviral properties) and secrete it before the virus induces apoptosis of the host cell. An early IFN response can lead to rapid viral clearance before its replication. Compared to children, adults have decreased IFN production and secretion.93 Together, the primed virus sensing and a preactivated immune response in children allow for early recognition of the virus, resulting in antiviral effects, reduced viral replication, and faster clearance in children.
Efficient adaptive immune response
In addition to heightened innate immunity, as stated earlier, children’s adaptive immunity may also serve as a protective factor. Children infected with SARS-CoV-2 generate a humoral response that is indistinguishable from that of adults with mild COVID-19, with comparable titers and functionality of anti-SARS-CoV-2 immunoglobulins.95 However, in contrast, adults with severe COVID-19 display significantly increased anti-SARS-CoV-2 immunoglobulin production, with increased immune complex binding and effector function, suggesting that hyperinflammatory humoral responses correlate with severity, and children are less likely to develop this hyperinflammatory serologic response.95 Additionally, children can rapidly produce protective anti-spike neutralizing antibodies (nAbs) after SARS-CoV-2 exposure, which assist in blocking invasion of the virus into the cell.96 Studies have shown that the early presence of nAbs positively correlated with patient survival and reduced persistence of SARS-CoV-2 RNA in nasopharyngeal swabs.97 This more efficient cellular and humoral response in children results in improved control of viral replication and viral clearance, which may explain the milder symptoms, and may also impact duration during which a child is contagious.17,96,98
Diagnostics
Screening
Testing and diagnosis of both symptomatic and asymptomatic children have proven to be essential in avoiding transmission of the virus in schools and communities. During the first 2 years of the pandemic, development of reliable rapid diagnostic tests was crucial in identifying infected individuals, prompting isolation and limiting spread of the virus. With initial testing measures, obtaining samples required high-resource utilization of healthcare workers and personal protective equipment, which limited the ability to perform large-scale testing, particularly in schools and colleges. Studies subsequently showed that SARS-CoV-2 detection in nasal swabs that were self-collected by school-aged children and adolescents demonstrated high concordance with results following collection by healthcare workers.99
This, along with other innovative detection strategies such as pooled sampling and wastewater detection, increased the potential to conduct repeated population-based screening in pediatric educational settings, without the need for labor-intensive sampling that disrupts children’s routines. Early detection proved to be an important step in breaking the chain of transmission and allowed schools to keep operating in times of high SARS-CoV-2 activity, while sparing important healthcare resources.
This, along with other innovative detection strategies such as pooled sampling and wastewater detection, increased the potential to conduct repeated population-based screening in pediatric educational settings, without the need for labor-intensive sampling that disrupts children’s routines. Early detection proved to be an important step in breaking the chain of transmission and allowed schools to keep operating in times of high SARS-CoV-2 activity, while sparing important healthcare resources.
Medical Workup
Like in adults, polymerase chain reaction (PCR) and rapid antigen self-tests (RATs) via nasopharyngeal swab are effective modes of testing in children. Additional workup, such as labs or imaging, is not indicated in most children with acute infection unless it is felt to change management. If certain indications such as respiratory distress, new oxygen requirement, or increased work of breathing arise, chest imaging can be helpful in differentiating the etiology (acute respiratory distress syndrome [ARDS] vs superimposed bacterial pneumonia vs viral pneumonia vs other). The main radiologic features in pediatric COVID-19 have been reported to be ground-glass opacities and consolidations.36,38 Similarly, laboratory workup is not necessary unless there is a particular concern. The typical abnormal laboratory findings in those with acute COVID-19 include lymphopenia with elevated creatine kinase (CK)-MB, C-reactive protein (CRP), aspartate transaminase (AST), alanine transaminase (ALT), D-dimer, and procalcitonin.36
Predicting Outcomes
There currently are no laboratory or radiologic tests that can predict the anticipated severity of disease; however, there are certain clinical symptoms and complications that may help predict unfavorable outcomes. ARDS and acute kidney injury (AKI) increased the odds of needing admission to the ICU. Shortness of breath increased the need for respiratory support. Underlying neurologic disease, CRP level of 80 mg/L or more, and D-dimer of 0.5 μg/mL or more increased the odds of progression to severe or critical disease.42 These factors, along with the clinical stability of a patient, can help triage patients to appropriate levels of care.
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