Since the beginning of the COVID-19 pandemic, children have been a key population of interest. Children have been drivers of many respiratory illnesses like influenza, and their social organization within schools and daycares have been known to proliferate epidemics. As the COVID-19 pandemic unfolds it has been noted that children exhibit fewer cases than what would otherwise be expected and generally have better outcomes. This lower rate of transmission can be partially attributed to the early closing of schools, which prevented spread but also limited information about prevalence among children. Furthermore, the pathogenesis of SARS-CoV-2 appears to be dependent upon expression of the ACE2 receptor, which is not highly developed in children and may result in lower viral loads. This causes many children to be asymptomatic, making identification of cases extremely difficult. These aspects of the COVID-19 pandemic make it difficult to determine the transmissible nature of the virus among children. This report comes as schools re-open of for the fall semester, and a comprehensive review of existing data can be helpful to drive strategy as re-openings occur. It should be noted that re-openings may present new data and insights to the spread of COVID-19 among children, and pediatric incidence and prevalence should be closely monitored as the pandemic continues to evolve.
The coronavirus that causes the current epidemic of Severe Acute Respiratory Syndrome is named for the crown of spike proteins that encapsulate the viral envelope. The spike protein attaches to a receptor in the body called Angiotensin Converting Enzyme 2 (ACE2), which coats the epithelial linings in the airways, lungs, heart, and kidneys. The ACE2 receptor functions in breaking apart the angiotensin hormone, which constricts blood vessels and increases blood pressure. While this site serves as the portal of entry into the host’s cardiovascular system, blockage of ACE2 receptors diminishes the body’s ability to regulate blood flow and oxygen exchanging capacity [1]. An inflammatory immune response is resultant of infection, and presented symptoms include fever, body ache, fatigue, nausea, and vomiting [2]. Rates and severity of symptoms vary across age groups and individuals, making identification of infection difficult without clinical testing.
Despite being drivers of other infectious respiratory diseases such as influenza, children have been observed to have a lower incidence rate of COVID-19 infection as compared with adults. Incidence and prevalence estimates vary and are difficult to ascertain, though figures regularly hold infection rates in persons under the age of 18 well under 10% of cases [3]. One of the principal challenges in identifying pediatric cases is that many are subclinical, either being completely asymptomatic or partially symptomatic (paucisymptomatic), in which a child is not recognized as having a COVID infection. A systematic review of 7780 pediatric COVID-19 patients showed that 19.3% of children were asymptomatic [4], and a multinational cohort study of 582 pediatric patients showed 16% of children did not present symptoms [5]. While these figures may appear low amidst large sample sizes, these findings may not be generalizable to the public due to subjects being sampled from hospitalized patients who are largely admitted for other conditions and receive higher levels of testing than the public. Prevalence figures appear to be contemporaneous with public incidence data [6], however, when paucisymptomatic cases are considered, subclinical infections can rise to nearly 70% [7]. Given the low prevalence and symptomatic presentation among children, paucisymptomatic cases may result in lower numbers of reported infections.
The incubation period of SARS-CoV-2 infection lasts from 2 to 14 days, where over half of all clinical cases present with fever and cough [5]. Computed tomography (CT) scans and x-rays show that nearly one-third of cases will have either patchy lesions in the lungs or ground-glass opacities – areas of liquid pooling in the lungs that appear black in scans and indicate decreased respiratory function [4]. The most prominent comorbidities are compromised immune systems and cardiac diseases, which account for 65% of underlying conditions seen in clinical patients. While asthma is a common comorbidity in patients with underlying conditions, it has not been determined to have a disproportionate effect on incidence as compared with non-asthmatic patients [8]. Mortality rates have remained low, with most studies observing a case fatality rate of less than one percent [1].
The differences in the infection rate, symptoms, and outcomes between children and adults are stark, and are further distinguished when stratified for age group. This is largely attributed to the variation of ACE2 expression in different sections of the respiratory system and other organ systems, as well as age-dependent expression. Maintaining that ACE2 expression has been observed to be inversely related with susceptibility to infection, ACE2 receptors were found to be expressed at much lower levels in the respiratory system of children than adults [9]. In both children and adults, ACE2 expression was found to be higher in the upper respiratory system and lower in the bronchial tree [10]. This is corroborated by molecular testing by polymerase-chain-reaction (PCR), where samples taken from different regions of the respiratory tract yielded higher concentrations of viral nucleic acid in the upper respiratory tract than the lower. Counter-intuitively, viral shedding was found to be higher in children younger than 10 than in older children and adults [11]. It should be noted that this detection was of viral nucleic acid rather than complete virus and may not reflect the transmission of infectious virus, potentially due to a lower prevalence of the ACE2 binding site necessary for infection as compared with adults. Collectively, the lower levels of ACE2 expression and lower respiratory tract viral loads indicate why infected children do not have the high inflammatory response and symptomatic presentation that adults do.
Transmission of SARS-CoV-2 has been one of the most impactful and elusive aspects of the pandemic. Infectious disease transmission has multiple components, and variations in each of these will dictate how far and how fast an outbreak will spread. Among adults, it has been estimated that 20% of the cases are responsible for 80% of transmission [12]. Whether this pattern holds true among children is yet to be determined, though due to the differences in incidence, pathogenesis, and age effects, it is doubtful that SARS-CoV-2 is spread among children to the same degree as seen in adults.
For an infectious disease to be transmitted, a person needs to be exposed to the pathogen, the pathogen must replicate within the host, and infectious virus must be shed from that individual. The existence of childhood exposures to SARS-CoV-2 has been demonstrated by the incidence of pediatric cases, though the degree to which the virus replicates within children is yet to be determined. Levels of ACE2 expression that are lower in children as compared with adults is indicative of a physiological mechanism that would lead to reduced susceptibility to infection. Lower levels of receptor expression necessary for viral replication would thereby lead to lower viral loads, though the viral load necessary for transmission is still unknown across age groups. Viral load can be quantified via PCR testing, though transmission is not guaranteed even with a high shedding of viral nucleic acid [13]. Site specific locations for detecting viral load indicative of transmissibility has also not been ascertained, as nasal epithelium does have higher nucleic acid content, though lower respiratory viral loads could be more telling [11].
An important area of study for age-stratified transmission is the household, as most infections are the result of prolonged, close contact between persons. The home is the most common location for the spread of SARS-CoV-2 because it is where one person most often infects many, known as the secondary attack rate. Children have been thought to be predominantly infected by adults, and adult-to-child transmission is suspected in 79% of cases, whereas child-to-adult transmission has been estimated in 8% of cases [3]. Interestingly, 33% of people in a home with infected persons do not become infected. Transmission largely occurs when the infected person does not know that they are sick, and 56% of COVID-19 cases are estimated to be transmissible before symptoms arise [14].
One of the looming questions about pediatric susceptibility is the issue of how schools will go about reopening in the fall of 2020. Even after six months of monitoring incidence trends, little is known about how COVID-19 will proliferate in school settings. Pathogenesis and household transmission trends can help to surmise how transmission will occur among children, although differences in environments and behaviors could result in stochastic outcomes. The early closure of schools was associated with lower levels of incidence, though this may be due to the tertiary effects of parents and caretakers remaining at home as well. Closures also came at the same time of lockdown orders, which may have masked the true effect of school closure on the path of the pandemic [15]. These closures were also correlated with lower incidence when the level of subclinical cases was assumed to be high, and the reproductive rate of the virus was not thought to be affected by median age [7]. While closures were an important step in the initial response to the outbreak of COVID-19, implementation of sustainable prevention measures is vital to resuming education, business, and daily lifestyle practices that drive societal function.
Contact tracing and transmission studies have shown that pediatric incidence of SARS-CoV 2 is largely due to adult behavior, therefore it is imperative that prevention measures are practiced by all age groups in order to safeguard the most vulnerable members of the population. A common topic of response is vaccine development, in which efforts are currently underway, though delivery of a safe and effective product normally takes years. Estimates place vaccine release sometime in 2021, yet efficacy studies and scalability of production make a release date a moving target. In the absence of a vaccine, reaching levels of natural herd immunity would require over 5.6 billion people worldwide and 200 million Americans to be exposed and recovered [16]. Given that evidence of long-term chronic effects of COVID-19 infection are beginning to arise, measures must be taken to avoid infection on the individual and population level as much as possible. Population level resistance by active immunity must be pursued by vaccination while preventing natural courses of infection which will increase morbidity and mortality.
Advances in testing are needed in order to facilitate school reopening, as closely monitored prevalence figures are critical for students to safely return to the classroom. While temperature checks have become common practice in many areas, the manifestation of symptoms often comes long after infectious periods in both children and adults and cannot serve as an effective screening method in the long term. The current gold standard for COVID-19 testing is PCR, which is highly advantageous in terms of sensitivity and turn-around time. However, it is difficult to perform repeated tests for a large population daily and turnaround times increase drastically when large populations place high-volume testing demand on laboratories with limited resources. Alternative testing methods are going to market, such as immunoglobulin tests that serve as a rapid screening tool at a much lower cost and can be administered on site to patients [17]. In the interim, the best methods for infection control in a reopening country remain social distancing practices and masks, though these present significant challenges for many aspects of daily life.
The reopening of the nation amid an ongoing pandemic brings about many ethical dilemmas that must be carefully considered with the welfare of key stakeholders prioritized. While the outlook for children has been somewhat favorable, policy makers and administrators of school systems need to be aware that the current data of pediatric prevalence of COVID-19 is largely generated from the shutdown period and summer break. The reintroduction of children to the school systems may bring about new patterns of transmission that have been previously unobserved, and continued surveillance of our youngest generations needs to be a high priority.
1. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
2. CDC COVID-19 Response Team (2020). Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR. Morbidity and mortality weekly report, 69(14), 422–426. https://doi.org/10.15585/mmwr.mm6914e4
3. Posfay-Barbe KM, Wagner N, Gauthey M, et al. COVID-19 in Children and the Dynamics of Infection in Families. Pediatrics. 2020;146(2):e20201576. doi:10.1542/peds.2020-1576
4. Hoang A, Chorath K, Moreiera A, Evans M, Burmeister-Morton F, Burmeister F, Navqi R, et al. COVID-19 in 7790 pediatric patients: A systematic review. E Clinical Medicine. Vol 24. doi.org/10.1016/j.eclinm.2020.100433
5. Götzinger F, Santiago-García* B, Noguera-Julián A, Lanaspa M, Lancella L, I Calò Carducci F, Gabrovska N, et al. COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. The Lancet. June 25, 2020. doi.org/10.1016/S2352-4642(20)30177-2
6. Sola AM, David AP, Rosbe KW, Baba A, Ramirez-Avila L, Chan DK. Prevalence of SARS-CoV-2 Infection in Children Without Symptoms of Coronavirus Disease 2019. JAMA Pediatr. Published online August 25, 2020. doi:10.1001/jamapediatrics.2020.4095
7. Davies NG, Klepac P, Liu Y. et al. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat Med 26, 1205–1211 (2020). https://doi.org/10.1038/s41591-020-0962-9
8. Papadopoulos NG, Custovic A, Deschildre A, Mathioudakis AG, Phipatanakul W, Wong G, Xepapadaki, et al. Pediatric Asthma in Real Life Collaborators (2020). Impact of COVID-19 on Pediatric Asthma: Practice Adjustments and Disease Burden. The journal of allergy and clinical immunology. In practice, 8(8), 2592–2599.e3. https://doi.org/10.1016/j.jaip.2020.06.001
9. Patel AB, Verma A. Nasal ACE2 Levels and COVID-19 in Children. JAMA. 2020;323(23):2386–2387. doi:10.1001/jama.2020.8946
10. Saheb Sharif-Askari N, Saheb Sharif-Askari F, Alabed M, Temsah MH, Al Heialy S, Hamid Q, & Halwani R. (2020). Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD. Molecular therapy. Methods & clinical development, 18, 1–6. https://doi.org/10.1016/j.omtm.2020.05.013
11. Heald-Sargent T, Muller WJ, Zheng X, Rippe J, Patel AB, Kociolek LK. Age-Related Differences in Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Levels in Patients With Mild to Moderate Coronavirus Disease 2019 (COVID-19). JAMA Pediatr. 2020;174(9):902–903. doi:10.1001/jamapediatrics.2020.3651
12. Althouse B, Wenger E, MIller J, Scarpino S, Allard A, H´ebert-Dufresne L, Hu H. Stochasticity and heterogeneity in the transmission dynamics of SARS-COV-2. arXiv 2020; 2005: 13689 (ePub ahead of print).
13. Merckx J, Labrecque JA, Kaufman JS. Transmission of SARS-CoV-2 by Children. Dtsch Arztebl Int. 2020;117(33-34):553-560. doi:10.3238/arztebl.2020.0553
14. Nishiura H. et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J. Infect. Dis. 94, 154–155 (2020).
15. Auger KA, Shah SS, Richardson T, et al. Association Between Statewide School Closure and COVID-19 Incidence and Mortality in the US. JAMA. 2020;324(9):859–870. doi:10.1001/jama.2020.14348
16. Bloom BR, Nowak, GJ, Orenstein W. When will we have a vaccine? - UNderstanding questions and answers about Covid-19 vaccination. NEJM. 2020. doi: 10.1056/NEJMp2025331
17. Pulia MS, O’Brien TP, Hou PC, Schuman A, Sambursky R. Multi-tiered screening and diagnosis strategy for COVID-19: a model for sustainable testing capacity in response to pandemic. Annals of Medicine. 2020; 52(5). doi.org/10.1080/07853890.2020.1763449
