Symptomatic and asymptomatic isolation of the virus in children infected with SARS-CoV-2 coronavirus

Although infants, children, and adolescents are susceptible to COVID-19 infection, only a few of them have severe symptoms.

Based on data from 22 medical centers in South Korea, the researchers determined the frequency of asymptomatic infection and the duration of symptoms and virus release in both asymptomatic and symptomatic children. The study involved 91 children with an asymptomatic, presymptomatic and symptomatic course of coronavirus infection of the upper and lower respiratory tract from mild to moderate severity. Infected children were identified primarily by tracking contacts with laboratory-confirmed coronavirus patients. The main advantage is the inclusion of asymptomatic (20 out of 91 [22%]), presymptomatic (18 out of 91 [20%]), and symptomatic children (53 out of 91 [58%]).

The South Korean public health system’s unique structure has facilitated large-scale testing, active contact tracking and testing, isolation, and direct monitoring of asymptomatic and children with mild symptoms in health facilities rather than in-home quarantine.

Not all infected children have symptoms, and even those with symptoms are not always recognized promptly:

  • Most of the infected children with symptoms showed symptoms on average 3 days before a PCR test confirmed COVID-19.
  • In the presymptomatic children, symptoms were absent for an average of 2.5 days before any symptoms appeared, despite the virus being detected.
  • Only a small proportion of the children (6 [7%]) were identified as infected when tested simultaneously with the onset of their symptoms.

It underscores the concept that infected children are more likely to go undetected with or without symptoms and continue their regular activities, contributing to the coronavirus’s spread.

The duration of coronavirus symptoms in children with symptomatic infection varies widely:

  • The average duration of symptoms for the entire cohort was 11 days.
  • The group of children who had no symptoms at the time of laboratory diagnosis had the shortest duration of symptoms – 3.5 days. This period was significantly faster than the duration of symptoms in children who developed symptoms simultaneously with the diagnosis – 6.5 days and those who had symptoms before the diagnosis-13 days.
  • Although most children with symptoms (41 out of 71 [58%]) had upper respiratory tract disease, there was no difference in the duration of symptoms in children with upper respiratory tract infection and mild or moderate lower respiratory tract infections.

The above suggests that even in children with mild to moderate lesions, symptoms persist for a long time.

How long does the SARS-CoV-2 virus last in infected children:

  • The virus was detected for an average of 17.6 days overall and for an extended time in all cohorts of children, regardless of the presence of the symptoms.
  • In asymptomatic children, the virus was detected on average within 14.1 days after the initial positive PCR test, and in 4 asymptomatic children (20%), the virus continued to be detected 21 days after the initial detection. The virus release duration in asymptomatic patients could be even longer because the initial infection date is impossible to know precisely.
  • There were no differences in the average duration of virus detection in children with upper respiratory tract infection (18.7 days) than children with lower respiratory tract infection (19.9 days).
  • Half of the children with upper and lower respiratory tract disease symptoms still released the virus after 21 days.

Both asymptomatic and symptomatic people can secrete the virus for long periods – from 2 to 3 weeks. In this study, 86 of the 88 children diagnosed (98%) either had no symptoms, or the disease was mild or moderate. These findings are significant for developing public health strategies to contain the spread of the coronavirus.

Who is more contagious: children or adults?

Chicago researchers examined nasopharyngeal swabs from 145 patients aged 1 month to 65 years with mild to moderate COVID-19 developed within 1 week of the onset of symptoms.

The researchers compared 3 groups:

  • children younger than 5 years (n = 46);
  • older children – from 5 to 17 years (n = 51);
  • adults aged 18 to 65 years (n = 48).

 

In PCR analysis, a positive reaction is detected by the accumulation of a fluorescent signal. Ct (cycle threshold) is defined as the number of cycles required for the fluorescent signal to cross the threshold, i.e., exceed the background level. Ct levels are inversely proportional to the amount of target nucleic acid in the sample, i.e., the lower the Ct level, the greater the amount of target nucleic acid contained in the sample.

The Ct value in PCR correlates with the viral load. Low Ct values mean a high viral load.

  • Ct < 29 is a strong positive reaction, indicating an abundance of the target nucleic acid in the sample.
  • Ct 30-37-positive reactions indicating a moderate amount of the target nucleic acid.
  • Ct 38-40-weak reactions indicating the minimum amount of the target nucleic acid. A high level of Ct can indicate both a state of infection and environmental pollution.

 

Ct values in children and adults:

  • Older children: 11.1 [6.3-15.7].
  • Adults: 11.0 [6.9-17.5].
  • Small children: 6.5 [4.8-12.0].

The highest viral load in the upper respiratory tract is in children under 5 years of age. The amount of SARS-CoV-2 in young children’s upper respiratory tract is approximately 10-100 times higher than the amount of SARS-CoV-2 in adults.

Immune suppression saves newborns and infants from COVID-19

Most infants infected with coronavirus have no symptoms, but they can infect others.

Usually, newborns’ and infants’ susceptibility to infections is associated with an underdeveloped or immature immune system. However, new data have shown that exposure to conditions results from active immunosuppression at an early age. This concept contradicts the traditional idea that the immune system is aimed at identifying and neutralizing pathogens. Instead, the immune system allows the body to tolerate the presence of non-pathogenic and pathogenic microorganisms.

Tolerance against infections

Natural protection against infection is aimed either at eliminating the pathogen or at preventing and reducing damage. Protection against diseases can be divided into two categories:

  1. the mechanism of clearance or resistance;
  2. the mechanism of tolerance.

The tolerance strategy is very reasonable. The resistance mechanism requires vast costs from the body and can lead to tissue damage and immunopathology. The tolerance strategy allows you to conserve the body’s resources and prevent side effects from eliminating the pathogen.

An optimal immune response requires a balance between pathogen clearance and immune system hyperactivity. However, this balance is not always possible. Therefore, to preserve the body’s resources, there is an alternative approach – the tolerance mechanism. Although this mechanism does not affect the pathogen’s amount, it can reduce the damage caused by infection or the immune system.

The weakened immune response in children allows them to avoid tissue damage and disease progression and protects them. Neonatal immunity is not underdeveloped but, on the contrary, is tightly regulated and dynamically reacts to pathogenic and non-pathogenic (for example, microbiome) stimuli. Such an intelligent and regulated immune system plays a crucial role in protecting growing infants from infections while at the same time preventing an excessive immune response. Therefore, the strategy of tolerance against infections in infants is a protective and intelligent mechanism for survival, continued growth, and development, taking into account infants’ limited resources.

The absence of a tolerance mechanism can lead to immunopathology. An example is 5-10% of neonatal sepsis cases, which may be associated with an excessive immune response. A tolerance strategy is vital to prevent an exaggerated immune response to pathogens. Otherwise, the resistance strategy may lead to increased morbidity and mortality among newborns.

A reduced, rather than increased, immune response may be associated with protection against specific pathogens and less immunopathology at an early age. For example, in infants and children, the hepatitis B virus rarely leads to acute hepatitis, whereas it is common in adults. The same is true for the hepatitis C virus: eliminating the virus without treatment is more common in infants than adults. The same was found for cytomegalovirus, Epstein–Barr virus, and chickenpox. In 75-80% of cases, newborns infected with cytomegalovirus have no clinical manifestations, and children secrete the virus for several years. That is due to the newborn immune system’s inability to control viruses’ replication in some organs. The Epstein-Barr virus in early childhood is asymptomatic or in the form of moderate disease, while in adults, it often manifests itself in acute infectious mononucleosis due to an excessive immune response.

Advantages of immunological tolerance in infants and children

During a natural birth, a newborn is exposed to millions of bacteria. This is how the interaction of the body with microorganisms begins. The fetus is practically not exposed to foreign antigens and, therefore, in the absence of tolerance mechanisms, bacterial exposure during childbirth can lead to increased inflammation of the mucous membranes and skin, where rapid postpartum colonization by microorganisms occurs. Therefore, a state of tolerance is necessary for the rapid adaptation of microorganisms.

The physiological abundance of immunosuppressive cells supports a highly regulated immune system at an early age. These regulatory cells can reduce the morbidity and mortality of newborns.

Newborns have a greater tolerance for bacteremia and can withstand bacterial load levels in the blood that are not possible for normal adults. Studies report a more significant bacterial load in newborns than in adults. For example, the bacterial load in sepsis in adults is usually 1-30 CFU/ml of blood, while in newborns, it is much higher – 50-500 CFU/ml, and in 1/3 of infected newborns, it exceeds 1000 CFU/ml. This fact becomes even more impressive when considering that 100% mortality in adult patients is associated with a bacterial load of > 100 CFU / ml of blood, while 73% mortality in newborns requires > 1000 CFU / ml of blood.

Children and adolescents may benefit from immune suppression but by a different mechanism. More frequent and more recent immunizations with live attenuated viral vaccines may promote the spread of long-lived myeloid-derived suppressor cells (MDSCs) in children and young adults. Populations of these cells exhibit immunosuppressive properties by suppressing pro-inflammatory cytokine production and T cell proliferation. Therefore, the presence of an innate immune regulatory mechanism in newborns and children can protect them from tissue damage associated with infections.

How is the choice of the effector immune response in newborns and children?

The immune system identifies the infectious pathogen and considers the immune and energy cost of its response. Any infection causes symptoms directly related to the damage caused by the pathogen or to an excessive immune response. Regulatory mechanisms form the optimal immune response in terms of magnitude, duration, and with minimal immunopathology. The immune system engages different effector responses depending on the effector/cost ratio. The idea is that an inexpensive response is generated first. If it does not help eliminate the infection, the next effector response with the lowest cost is generated.

In the absence of immune regulation, the recognition of pathogens by macrophages and dendritic cells can cause more expensive effector reactions in newborns. Therefore, immunosuppression in newborns and infants is a balanced choice of the immune system, taking into account the body’s costs.

Iwasaki and Medzhitov proposed an exciting model illustrating immune effector reactions with different costs. The secretion of IgA antibodies and antimicrobial peptides is an inexpensive defense mechanism. When this mechanism cannot protect the body from pathogens, the next immune response will be induced at the lowest cost – for example, tissue macrophages. Attracting neutrophils and other immune cells to the infection site is the following cheapest immune response, followed by the reaction of cytotoxic T cells and Th17 T helper cells.

Immune protection against life-threatening pathogens is energetically expensive, and there is a trade-off between investing in a rapid immune response and the growth and development of infants and children. Therefore, the choice of the type of effector immune response in newborns and children should be less expensive in energy, given the high energy costs for growth and development.

Infants, children, and young adults are protected from COVID-19

Newborns and infants infected with SARS-CoV-2 may benefit from their immunological tolerance.

Despite thousands of reported cases in China (> 20,000 cases by February 6, 2020), only nine infants (0.05%) were hospitalized with COVID-19. Among these cases, four infants had a fever, two had very mild upper respiratory symptoms, one had no signs, and no information was provided for the last two.

In another report, an infant developed a case of neonatal COVID-19 infection from an infected mother 36 hours after delivery. However, the newborn did not have any respiratory symptoms.

A third study reported that among the > 44,000 confirmed cases of COVID-19 in China, 0.9 and 1.2% were aged 0-10 and 10-19 years, respectively.

In general, after infection with COVID-19, symptoms in children are less pronounced than in adults, and in most cases, COVID-19 is asymptomatic, but these asymptomatic children can play an essential role in the spread of the virus in society.

Newborns, children, and young adults (< 18 years old) differ from an immunological perspective. Although newborns and infants may benefit from the physiological abundance of immunosuppressive cells, these cells gradually disappear with age. Therefore, other factors should explain the milder or asymptomatic infection in older children. A recent report suggests that trained non-specific innate immunity after vaccination with live attenuated measles, mumps, and rubella (MMR) vaccines may protect adolescents from COVID-19. Live attenuated vaccines, such as MMR, rotavirus, smallpox, and tuberculosis (BCG) vaccines, can provide non-specific protective immunity. Another possibility is that such non-specific effects lead to the induction of long-lived MDSCs. MDSC-mediated immunosuppression reduces the excessive inflammatory response to pathogens and may be protective, as COVID-19 is associated with severe lung inflammation and sepsis.

Risk of COVID-19 infection in adults and children

Angiotensin-converting enzyme 2 (ACE2) is expressed in many organs, such as the heart, lungs, intestines, and kidneys. SARS-CoV-2 binds to the ACE2 receptor to enter the cell and gets the opportunity to join the cell through ACE2 and suppresses the expression of ACE2 on the cell surface, so this enzyme cannot exercise its protective role in organs. The suppression of ACE2 in the respiratory tract is associated with neutrophil infiltration, leading to the accumulation of angiotensin II and lung damage.

Retrospective studies of confirmed cases of COVID-19 have shown that children do not get COVID-19. Although the mechanism underlying these observations is unknown, it has been suggested that ACE2 expression is different in infants and children compared to adults. However, there is no clear evidence for the effect of age on ACE2 expression in the lungs, except for a recent study that reported no differences in ACE2 activity in bronchoalveolar lavage fluids newborns, children, and adults with acute respiratory distress syndrome. Another supporting evidence for the young and elderly expression of ACE2 is the decrease in androgens and estrogens with age. Both of these hormones increase the expression of ACE2. Thus, their reduced production with age may lead to suppression of ACE2 expression.

Animal studies show that decreased ACE2 activity or loss of ACE2 leads to neutrophil recruitment, increased vascular permeability, and pulmonary edema, but in turn, the addition of exogenous ACE2 reverses this inflammatory response. SARS-CoV infection has been reported to inhibit ACE2 activity in mice’s lung tissues, accompanied by lung damage. The SARS-CoV and SARS-CoV-2 coronaviruses are similar, so there is a possibility that SARS-CoV-2 also suppresses ACE2 expression, resulting in lung damage.

The role of ACE2 seems complicated. On the one hand, ACE2 may increase the risk of SARS-CoV-2 infection, given the mechanism of virus entry into the cell. However, on the other hand, ACE2 can reduce lung damage after infection.

Conclusions

Despite the susceptibility to infection in infants, children, and adolescents, COVID-19 is mostly asymptomatic or mild. The immune system in children behaves differently than in adults. Infants respond to microorganisms with immunological tolerance rather than a resistance strategy. More frequent and recent vaccinations of children and young people can lead to immunity, promoting immunosuppressive cells. The physiological abundance of MDSC immunosuppressive cells, a tightly regulated immune system, and exposure to weakened vaccines can strengthen trained immunity to limit the over-immune response to COVID-19 in the young.

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