. 2021 Dec 28;41(2):e36–e45. doi: 10.1097/INF.0000000000003413

TABLE 1.

Summary of Mechanisms Proposed to Contribute to the Age-Related Difference in the Severity of COVID-19

Mechanisms with the strongest supporting evidence to date
1. Differences in innate immunity
In response to SARS-CoV-2, children have:
• a stronger mucosal innate immune response, which helps clear the virus^9,16,23,24
• lower levels of neutrophils, which have been associated with microangiopathy and thrombosis^27,28,32
• differences in cytokines levels with a lower tendency to develop a cytokine storm^{26–29,33,35}
2. Differences in adaptive immunity
In response to SARS-CoV-2, children have:
• higher lymphocyte counts with a higher proportion of naïve T cells, T regulatory cells and T follicular helper cells^48–50
• lower T cell responses to spike and ORF1 proteins^16,35,49,50 Results from studies are inconsistent in relation to:
• T cell responses against nucleocapsid and membrane proteins; studies show both lower⁵⁰ and higher^16,35,49 levels in children
• differences in SARS-CoV-2-specific mucosal and serum antibody levels^{27,28,32,35,37,38,44,58–62}
3. Heterologous immunity and off-target effects of vaccines
Children have:
• more recently been vaccinated with BCG, MMR, Tdap and other vaccines which might offer indirect protection against COVID-19^{67,68,70,75–78,81–87,96}
• more frequent recurrent or concurrent infections which might induce an enhanced state of activation of the immune system¹⁰¹
4. Differences in the endothelium and clotting function
Children are:
• less prone to endothelial damage and abnormal clotting¹¹⁰
Mechanisms with less supporting evidence to date
1. Pre-existing immunity from exposure to commonly circulating human coronaviruses
• Although antibodies against HCoVs can be cross-reactive, they might not be cross-neutralizing^{16,35,49,58,118,135–139}
• Role of cross-reactive T cells in relation to SARS-CoV-2 also remains unclear^121,122,149
• There is conflicting evidence on whether children or adults have higher levels of antibodies and T cells cross-reactive between HCoVs and SARS-CoV-2^{35,118,128-130}
2. ACE2 and TMPRSS2
• There is conflicting evidence on whether children have lower numbers and different distribution of ACE2 and TMPRSS2 across body sites^{9,16,24,154,156–158}
• ACE2-angiotensin system is affected by many factors other than age^{154–157,160,164–170}
• ACE2-angiotensin system is complex and also involved in regulating immune responses¹⁷¹
3. Viral load
• Children and adults have similar viral loads and shedding from the respiratory tract^16,179–181

ACE2, angiotensin-converting enzyme 2; BCG, Bacillus Calmette-Guerin; COVID-19, coronavirus disease 2019; HCoVs, human coronaviruses; MMR, measles-mumps-rubella; ORF, open reading frame; SARS-CoV-2, severe acute respiratory tract coronavirus 2; Tdap, tetanus-diphtheria-pertussis; TMPRSS2, transmembrane serine protease 2.