14 Aug 2020; Updated 22 Sept 2020
The media and politics love dramatic shifts, and in that context, the general narrative suggests the science has been shifting around COVID-19 and children. But, in fact, the science has provided a relatively stable picture, with clear trends indicated early in the pandemic. Over time, these trends have become more detailed and more reliable, reflecting children (0-18 years) are not a uniform group when it comes to COVID-19.
Age disaggregated data reflects significant differences across multiple contexts. And while there is ample proof of concept that all children can and do get infected, the rest of the conversation is urgently needed in order to inform evidence-based risk reduction strategies.
There are three dimensions, along which, to understand differential effects of age on children’s COVID-19 risk: the likelihood of transmitting it to others, the susceptibility to acquire the infection, and the severity of infection when they do get it.
Among these three dimensions, the largest discrepancy between pediatric age groups relates to transmission to others. Older children (10- 17 years) have been implicated as transmitters of the virus, similar to adults in numerous outbreaks. In contrast, while younger child to adult transmission (5-9 years) can and has occurred, their role as transmitters-- and particularly as sources of outbreaks (e.g., index cases)- has been very rare. The evidence for this is strong, and includes preschool data from the US, global data from school settings as well as evidence of viral load as a poor proxy on it's own as a measure of infectiousness in children [1-11, 33].
Younger Children in School & Childcare Settings: Daycares and preschools in the US might be expected to provide an upper bound on elementary school infection rates—operating with few resources and demographics skewed towards essential workers. However, there is reassuring data from daycares and preschools in the US, where there has been relatively modest infection rates.
In California, statewide data on childcare facilities report ~1 COVID positive infection reported per 20 open childcare facilities over a five month period . At a county level, while these numbers vary based on community infection rates, a more clear picture emerges in terms of how infection is spreading. For instance, in Alameda County, which has 14,214 COVID-19 positive cases as of Aug 11, 2020, the infection rate is 1 infection in approximately 10 childcare facilities over a 5-month period.
Interestingly, of the 40 infections traced to childcare facilities in Alameda County, 20 were facility staff but less than 11 cases reported were among children and less than 11 cases reported among children’s parents [12-13]. In other words, infections have not been spreading peer to peer in these settings nor have children been transmitting to parents in their households.
Given that the most risk for transmission is within a household setting both in terms of exposure intensity and time, it's noteworthy that the infection rates reported for parents of children attending childcare facilities are also unremarkable. Thus, while children may go under the radar with milder to no symptoms, it's harder to explain a role of silent spreading children when their household members are not being infected.
This picture from California childcare facilities is consistent with COVID-19 transmission data from elementary school settings in 10 countries early in the pandemic with active caseloads in schools (Austrailia, Ireland, Finland, France, Singapore) as well as school re-opening data (Belgium, Denmark, Greece, Norway & Switzerland) [15, 35, 40]. In fact, these findings point to the largest vulnerability for staff coming from other staff .
- An investigation of two infections in a Finland school settings identified no secondary infections when the index case was a child but a 16% secondary infection rate where the index case was an adult .
- An Australian virologic and serology investigations of 27 SARS-CoV-2 infected children and adults attending school when they were infectious, found 18 secondary infections among 1448 close contacts tested. The investigation, which included one outbreak within an infant/ childcare facility, identified an attack rate lowest among child to child contacts (2/649; 0.3% secondary attack rate), followed by child to staff contacts (1/103; 1% secondary attack rate), staff to child (8/536; 1.5% secondary attack rate) with the highest risk of transmission onwards between staff (7/160; 4.4% secondary attack rate) .
- A French study of an infected 9 year old included contact tracing of 112 contacts in 3 different schools attended. No identified contacts acquired the infection .
In contrast, older children and adolescents in secondary or high schools have been characterized by outbreaks in Germany, Israel, France and the US . This pattern with older children could be seen early in the pandemic. A serology outbreak investigation in a Northern France high school community, early in the pandemic, identified a high infection attack rate (~40%) among 15-17 year olds (N=205) .
An age disaggregated lens of outbreaks in schools implicates older children, adolescents and adults as transmission points for SARS-CoV-2. And while outbreak evidence clearly offers proof of concept that the virus can and will spread through any group of children-- for younger children--outbreak data implies this is an issue of susceptibility versus efficient transmitters.
Outbreak data related to younger children (5-9 years) suggests a particular condition is required: an environment amplified for infection spread. It is not yet clear that these amplifiers are needed for outbreaks involving middle school age children but the evidence does implicate teenagers in community transmission and school outbreaks.
What about high viral load levels in young children?
Conventionally, high viral load is a marker both for severity and transmission. Both are called into question when it comes to SARS-CoV-2.
Viral loads in asymptomatic and symptomatic individuals have been reported at similar levels yet severity of infections differs. The second contradiction relates to transmission. Pediatric cases show high viral loads but global evidence clearly demonstrates children are not driving transmission. But these contradictions are not new. High viral loads were also seen in pediatric SARS infections (2003) . And, similar to SARS-CoV-2, SARS (2003) cases of children transmitting the virus to adults were rare .
Why this may be the case for children is the unanswered question. However, there are key scientific insights contributing to a better understanding the viral load contradiction in children.
One potential factor in these contradictions is simply that viral load counts are somewhat misleading in the case of SARS-CoV-2. Viral load picks up any remnant of viral RNA, whether it’s infectious or not. Evidence from a SARS-CoV-2 study in Hong Kong indicated adults with mild infections had active infectious virus for less than 10 days after symptom onset but viral RNA for many weeks afterwards . In other words, viral load alone—may offer a general approximation of an infection timeline but not an indication of infectiousness.
An alternative hypothesis is that variation between pediatric and adult infection severity are driven more by immune responses than by viral replication levels . Infection severity—frequently characterized by the second phase of a SARS-CoV-2 infection-- has been linked to an overreaction of the adult immune system (e.g., inflammatory response via cytokines, likely from lung tissue . This immune system overreaction is not seen in children [44-45]. It’s notable that pediatric lung and intestinal tissues have higher levels of regulatory T cells. These T cells may help in suppressing immune responses [44, 46].
Other immune response factors associated with severity of infections are likely lower in children than adults (e.g., neutrophil counts) and occur with much less frequency (lymphocytopenia) . For instance, among a sample of 171 COVID19 pediatric cases, 6 developed lymphocytopenia [44, 47].
A second dimension may be that viral replication itself may be more fluid in pediatric cases due to co-infections prior to and/or during an active SARS-CoV-2 infection.
Frequent infection exposures for children may play a role in how the body’s immune response is mounted to attack SARS-CoV-2 . One hypothesis is that T-cell responses from earlier infections can more efficiently respond to SARS-CoV-2 from the start (e.g., cross-reactive T-cells) [49-50]. While it remains unclear to what extent prior seasonal coronaviruses may act protective with SARS-CoV-2 infections, studies do show when infected with SARS-CoV-2, there is cross-reactivity in the body with seasonal coronavirus antigens (hCoV-OC43) .
In addition, it may not just be prior exposures but also the inter-play of two infections co-occurring, where one virus can suppress another one to certain degrees. Analysis of rhinovirus and influenza A during the 2009 H191 pandemic in Europe demonstrated this principle of viral interference. Among 8284 positive respiratory samples examined, findings showed the antiviral reaction to rhinovirus was protective with influenza A infection. The authors found after 5 days of rhinovirus, a ~ 50,000 fold decrease in influenza A H1N1 viral RNA .
SARS-CoV-2 is infectious but at the same time, a fragile virus. Mathematical modeling studies reflect SARS-CoV-2 has a more easily suppressed growth rate (1.8/ days for SARS-CoV-2 compared to influenza, 11.9/ day and rhinovirus, 13.6/ day) . This fragility compared to other common viruses, alongside more optimal immune responses, offer important preliminary insights to account for milder infections in children.
A second dimension emerging with differences between pediatric age groups relates to susceptibility.
There is preliminary evidence to suggest reduced susceptibility among children under 10. Population based screenings among 6% of Iceland populations found no cases under 10 years of age, while 0.8% of children >10 tested positive . Similar findings emerged from a population screening in Italy (Vo) .
This is consistent with findings from three seroprevalence surveys to detect SARS-CoV-2 IgG antibodies in Italy, Spain and Switzerland [18-20]. In Switzerland, more explicit pediatric age categories in a seroprevalence survey found 5-9 year olds (n=123) to have a lower risk of seropositivity (RR: 0.32 (95%CI: 0.11-0.63)) compared to 20-49 year olds. This was lower than the relative risk for 10-19 year olds (n=233), which had a relative risk of 0.86 (0.57-1.22) compared to 20-49 year olds. Interestingly, among 5-9 year olds testing negative, 21 had a COVID positive member of their household .
However, protection is not immunity. One of the few studies to actually produce generalized community level data indicating infection rates across different groups of children is a report from Dong and colleagues on 2,143 children in Hubei province in China early in the pandemic (Jan 16- Feb 8, 2020). Those under 1 year had a 10.6% infection rate, children 1-5 year olds reported 7.3%, 6-10 year olds reported 4.2% and 11-15 year olds reported a 4.1% infection rates . This important, early report provided proof of concept that children may be shielded from the severity of infection, but not immune. In its aftermath, outbreak data has repeatedly confirmed that if an environment amplifies COVID exposure, the infection will spread through any cohort of children regardless of age or health status. Recent instances of this include:
- An outbreak in an Australian childcare facility resulted in six staff and seven children infected, where 3 children infected were infants under 1 year and asymptomatic .
- An outbreak at a Georgia sleepaway camp with more than 600 teens and children-- infected both children and staff (age range 6-17 years), where young children (6-10 years) had a 51% attack rates, while 11- 17 year olds had a 44% attack rate. However, what is equally important is that attack rates were highest (53%) in the largest cabins (16-26 persons), where there was no systematic ventilation. Given that the youngest campers were housed in the largest cabins, it provided a highly efficient environment for infection spread to be amplified. The first symptomatic case with confirmed infection was a teenage staff member, who had been at the camp for 7 days with 258 teenage and adult counselors for orientation. Two of the seven days also had younger campers were also in attendance .
- An Israel high school outbreak, where dangerous infection spread conditions via recycled air and crowded classroom led to an outbreak among 153 students (12-18 year olds) (13.2% attack rate) and 25 staff (16.6% attack rate) ;
While these scenarios are stark reminders of what occurs when there are no or poor mitigation measures in place, there is equally powerful data to suggest strategic mitigation can be effective with SARS-CoV-2, particularly for younger children. Fortunately, there are decades of research from TB, influenza and SARS to draw from to chart out how to avoid amplifying efficient aerosol and droplet transmission in the environment (see here).
A third dimension, severity of infection is largely characterized by relatively muted infections across pediatric age groups. However, in the US, pediatric infections have higher hospitalization rates compared to other countries. Wide health disparities between communities play a large role.
Hospitalization data from 14 states in the US have been higher for children under 5 (12.9 per 100,000) compared to that for 5-17 year olds (7 per 100,000) as of August 1, 2020. The same CDC mechanism reported hospitalization rates for 18-29 year olds at 55.9 per 100,000 and 207.4 per 100,000 for 50-64 year olds during the same time periods (CDC data from 14 US states) .
Severe SARS-CoV-2 infections are disproportionately within minority communities in the US, and correlate with higher prevalence of pediatric obesity, diabetes, and asthma. These are also communities with some of the greatest work exposure risks (e.g., parent inability to work from home). Among 46 pediatric ICUs in the US and Canada from March to April 2020, 83% of US pediatric patients admitted to the ICU had a co-morbidity .
Younger school children (5-9 years) have been largely associated with more muted infections, but it has also been the group most associated with a rare complication-- multi-system inflammatory syndrome (MIS-C). In the US, 1 in 80,000 have been hospitalized with a MIS-C diagnosis and 1 in 5 million have died as a result of an MIS-C diagnosis as of CDC data current as of August 6, 2020 . For comparison, influenza mortality is reported at 2 per 100,000, according to US CDC . But, even with underlying conditions present in only a small portion of pediatric cases of MIS-C, over 70% of these cases in the US are Latino/ Hispanic or African American . High caseloads of MIS-C in the UK have been associated with minority communities as well .
Moving forward: Better systematic data for elementary & middle school students
While researchers continue to attempt to answer the 'why' behind these discrepancies in more detail, the data related to transmission, susceptibility and severity consistently indicate differential age effects among infants, children and adolescents.
In practice, this can translate into a simple starting point to move forward: Amend COVID-19 data collection to reflect developmental stages for school children -- by elementary, middle and high school age -- instead of 5-17 years. This is critical in countries such as the US, where infection control remains tied closely with economic priorities. It will allow schools and health departments to use a scalpel instead of an axe to inform future decisions.
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