14 Sept Episode 172 Why is SARS-CoV-2 less severe in children?

Dear colleagues,

In this episode, I will not come back on MISC, but rather focus on why severe cases and mortality of COVID in children were rare.  This is  quite in contrast with for instance the 1918 Spanish Flu, which shows an U-shaped mortality curve in function of age (see first picture).  Is this relatively related to viral or host factors?   

1. Viral dynamics in children

Ep 172-1: Irfan provides a comprehensive review of 90 studies in J Global Health, showing that children have a lower risk on infection than adults, while the risk for adolescents is comparable.  Nevertheless, the relative risk remains substantial for most settings (around 0.80), with the exception of pre-school day care (RR = 0.53) and households (RR = 0.62).  Hence, for sure, children are not marginal “bystanders” in the pandemic.  

Ep 172-2: Studies on viral load in children (in the pre-delta era):

1. A thorough comparison by Chen in Elife shows that disease severity, but NOT age and sex are associated with higher viral load, especially in the lower respiratory tract. 
2. Eckerle et al in CID March 2021: viral load in nasopharyngeal swabs from symptomatic children and adults is sufficiently high for transmission, but adults > adolescents > children.

(See second picture)

3. Euser in a retrospective study from the Netherlands over 2020 observe a clearly lower viral load (Ct value) in children < 12 years old, independent from symptoms  (see third picture) Interestingly:

• the median Cp-values between the >79- and <12-year-old populations differed by more than four PCR cycles, suggesting an 16-fold difference in viral load.
• the proportion of children aged <12 years with a low load (Cp-value >30) was higher compared with other patients (31.1% vs 17.2%), suggesting that antigen test (with lower sensitivity will be more often false negative in children.  

Ep 172-3:  Some data on delta in children:

1. Sheikh in Scotland (June in Lancet): reports that delta was relatively more common in children 5-9 years old
2. A nationwide study in US over the last year shows that the SARS-CoV-2 incidence is sharply rising again in children since June (advent of delta) and is reaching the level of the past Winter peak (also shown in the fourth picture).  Moreover, there is a clear inverse relation between the number of children of all ages admitted to the emergency department and the vaccination percentage of the adult population.

Provisional conclusions:

• Children do participate fully in the pandemic, but their risk on infection and their viral load is generally considered lower. 
• These virological differences alone cannot explain the lower pathogenicity in children.
• Vaccination of the adult population can indirectly protect children.

2. Immune factors

2.1. Adaptive immunity:  

Ep 172-4: Fraley in Cell Mol Imm show that both uninfected adults and children have low levels of cross-reacting antibodies against nucleoprotein and S2, but even less against S1 and the receptor binding site.  Levels in children were rather lower than in adults.  At first view, it seems unlikely that those cross-reacting antibodies in children could protect against SARS-CoV-2.

Ep 172-5: Weisberg et al in Nat Imm: children with mild or severe (multi-system inflammatory syndrome or MICS) disease develop measurable antibody responses, comparable with adults after mild disease, but much lower than adults with severe disease.   The in vitro neutralizing capacity of post-infection antibodies in children is rather weak.  Hence, also unlikely that infection-induced antibodies are potently protective in children.

Ep 172-6: Carolyn Cohen in Nat Comm also find lower CD4+ and CD8 + T cell responses in children as compared to adults. Due to lower beta-Corona-cross-reactive  baseline?   

• The quality (polyfunctionality and exhaustion markers) of T  cell responses was however similar in children and adults.  
• Children presented with higher recruitment of T helper follicular cells (important for antibody maturation).

• Also lower levels of inflammatory monocytes in children.

→ Reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis ?

In view of low adaptive immunity in children; what about parameters of innate immunity?

2.2. Innate Immunity

2.2.1. Peripheral blood parameters

Ep 172-7: Pierce et al confirm that hospitalized children had a shorter length of stay, decreased requirement for mechanical ventilation, and lower mortality compared to adults.  Upon peripheral blood analysis:

• Neutralizing Ab and T cell responses are lower in children.
• Children present higher levels of the cytokines IL-17A and IFN-gamma in their blood and those cytokines are inversely related to neutralizing Ab and age,

→ It is not immediately clear which cells are the source of these cytokines: could be T cells, NK-T cells, neutrophils etc. 

→ We know that IF-gamma and IL17A are involved in mucosal immune protection….

Ep 172-8: Neeland in Nat Comm find reduced circulating monocytes, natural killer cells and dendritic cells, but increased proportion of activated neutrophils  during acute phase of COVID in children.  Activated neutrophils were also observed in exposed uninfected children and adults.

→  These findings are interpreted as evidence of “redistribution”: these innate cells may disappear from the circulation to concentrate in the site of infection.   Presence of immune and inflammatory cells in broncho-alveolar lavage has been shown in adult (but not pediatric) COVID patients.

Ep 172-9:  Silverstein in medRxiv suggests that so called “innate lymphoid cells” (ILC are the “innate counterparts of Th1, Th2 and Th17) are crucial for “disease tolerance” in SARS-CoV-2 infection, based on:

• The fact that they decrease strongly with age (in contrast with T cells)
• Were selectively depleted in adult and pediatric hospitalized patients
• Correlate inversely with inflammation and duration of hospitalization: the mlore vILC are depleted, the more inflammation and longer the stay.
• Produce amphiregulin, that maintains integrity of epithelial barriers in lung and gastro-intestinal tract: so ILC depletion may be negative for mucosal repair during viral infection.

Clearly, all these data on peripheral blood point to some association/involvement of various aspects of innate immunity in COVID, but they do not provide direct evidence of what happens at the site of infection.

2.2.2. Mucosal parameters

Ep 172-10:  Carl Pierce et al in JCI Insight provide direct evidence of more vigorous anti-viral and inflammatory response at the nasopharyngeal mucosa in children versus adults: besides confirming higher IL17-A and IFN-gamma (just like in blood see Ep 172-7) they now show also higher type 1 IFN and higher IL1beta and IL-18 at the mucosal site. 

Remarkable, levels of IgG and IgA antibodies were similar in children and adults.

Ep 172-11:  A very elegant paper by Loske in Nature Biotechnology showing that the nasal mucosa in children is “pre-activated” for antiviral responses, because of higher basal expression of “RNA sensors” such as MDA5 and RIG-I in epithelial cells, macrophages and dendritic cells  (amongst other differences, such as presence of specialized CD8 T cells).

This is a groundbreaking paper, because it goes beyond associations and strongly suggests that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

As a third minor point, I will briefly discuss the link between Down syndrome and COVID.

3. Down syndrome and other mental disabilities

Ep 172-12: Williamson in BMJ

• Adults with learning disability and those with Down’s syndrome or cerebral palsy have markedly increased risks of hospital admission and death from covid-19
• Similar patterns were observed for children, but absolute risks of covid-19 hospital admission and death were small

Ep 172-13: Two cases of MISC like syndrome in pediatric Down patients: characterized by neutrophilia, B cell depletion and inflammatory markers.  A similar (but less pronounced) pattern is seen in uninfected Down children.

Ep 172-14: A general overview of immune abnormalities in Down syndrome, that may underly the tendency of increased susceptibility to respiratory infections, including Respiratory Syncytium Virus, Influenza and SARS-CoV-2. 

Clearly, chromosome 21 encodes various cytokine receptors and micro-RNA that regulate various aspects of humoral and cellular immunity (see Fig 2 and  4), resulting in a complex immune dysregulation (Fig 3).

Some conclusions   

1. Adaptive immunity (SARS-CoV-2 antibodies and T cells) is rather weaker in children than adults:
   • This may be linked to lower previous exposure to other beta-Coronaviruses and/or to the benign course of the SARS-CoV-2 itself (we see also weak T and B responses in mildly infected adults).
   • It may be beneficial, because of lower (late) inflammatory response.
   • Implication for post-infection protection against reinfection not clear

2. Children have clear-cut signs of rapid mucosal (and systemic) antiviral responses
   • This is due to a higher expression of viral RNA sensors in mucosa
   • In this way, the SARS-CoV-2 is “beaten” before it can downregulate and interfere with the human interferon response
   • Because of this early viral control, a late inflammatory response is prevented (and adaptive immunity is not fully activated)?

3. Children with Down are more susceptible to SARS-CoV-2 pathology (and to other respiratory viruses, because of a complex immune dysregulation with decreased antiviral responses and increased inflammation.

I hope this was useful?

Best wishes,

Guido