Increased endothelial damage with age

Susceptibility to excessive coagulation increases with age

Importance of endotheliitis and microthrombi in pathogenesis of COVID-1929 30

Association between conditions that affect the endothelium, such as diabetes and hypertension, and severe COVID-1935–37

Age-related changes in coagulation consistent with age gradient of severe COVID-1938

Thrombotic complications, such as heart attacks and strokes, in COVID-1929 31–34

Vasculitic skin manifestations in COVID-1939–44 53 223

Age-related differences in expression, affinity and distribution facilitate SARS-CoV-2 entry into cells

Expression and affinity of ACE2 increase with age55 57–59

Variants in the ACE2 gene are linked to severity of COVID-1968

Pneumonia caused by CoV NL63 (that also binds to ACE2) is more common in adults compared with young children224

TMPRSS2 expression on nasal and lung epithelial cells likely increases with age58 59 71

ACE2 has anti-inflammatory properties that protect against ARDS, as well as SARS-CoV- and influenza-associated lung injury in animal studies64 65

Less ACE2 leads to higher levels of angiotensin II which is positively correlated with viral load and organ injury in SARS-CoV-2-infected patients67

Non-neutralising HCoV antibodies facilitating cell entry and viral replication (antibody-dependent enhancement)

Reinfection with commonly circulating HCoV is frequent76 77

Higher levels of neutralising and non-neutralising CoV antibodies have been found in adults, especially elderly compared with children78 79 148

Cellular immunity to SARS-CoV-2 found in some non-exposed individuals88–90

Higher numbers of cross-reactive T cells found in elderly80

Children with COVID-19 have a less robust T cell response to spike protein (lower frequency of CD25⁺ and IFN-γ-producing CD4⁺ T cells), lower neutralising antibody levels and less antibody-dependent enhancement78

Decline in innate and adaptive immune function in elderly leads to reduced SARS-CoV-2 clearance

Chronic proinflammatory state associated with age predisposes to cytokine storm

CMV’s effect on T cells leading to reduced capacity for immune responses to novel viral infections such as SARS-CoV-2

Increase in abundance and activity of NLRP3 inflammasome with age might be associated with severe COVID-1999 100

Diseases associated with inflammaging (eg, cardiovascular, diabetes, obesity) are risk factors for severe COVID-1997

CMV causes clonal T cell proliferation and a reduction in naïve T cell diversity103

CMV increases inflammatory-mediated cytokines such as TNF-α and IL-6106

Likely related to endothelial damage

Younger age groups less often suffer from the comorbidities that have been associated with severe COVID-19 in adults36

Younger age groups with these conditions do not appear to develop severe COVID-197 107–109

Lower vitamin D levels

Vitamin D is reduced in older age groups, as well as in obesity and chronic kidney disease, both of which are associated with more severe COVID-19117 118 120

Vitamin D levels lower in SARS-CoV-2-positive individuals and negatively correlated with severity of radiological findings124 125

Infants less likely to be vitamin D deficient than older age groups, as supplemented in many countries225

Stronger innate, trained immune response leading to more effective virus containment/clearance

Weaker adaptive immune response and therefore less hyperinflammation

Lower proinflammatory cytokine responses (cytokine storm)

Children with COVID-19 have higher levels of IL-17A and IFN-γ78

Some other infections are also less severe in children, for example, dengue, Epstein-Barr virus, hepatitis A, measles, Legionnaires’ disease, polio, varicella

Age-related difference in immune response does not mirror age gradient in COVID-19 in which lower severity extends into early adulthood

Differences in the immune response do not protect against other respiratory viruses to which children are generally more commonly and more severely affected28

Stronger innate immune response may be both protective but may also worsen cytokine storm32 136 138 139

Children are not less prone to develop a cytokine storm leading to ARDS with RSV and influenza infections138 140

Immunocompromised not at as high risk of severe COVID-19 as would expect if this were principal mechanism226

More frequent infections with other pathogens may help fight SARS-CoV-2

Children infected with SARS-CoV-2 often have co-infections with other viruses or mycoplasma141 142

Recurrent viral infections could lead to epigenetic changes in trained immunity making it more effective in clearing SARS-CoV-2134

Pre-existing neutralising antibodies and T cell immunity to commonly circulating HCoV in younger age groups cross protect against SARS-CoV-2

Antibodies to commonly circulating CoV2 are cross-reactive with SARS-CoV-2, but rarely cross-neutralising146–148

No difference in antibody levels against HCoVs between children infected with SARS-CoV-2 and those who are not150

Higher levels of neutralising CoV antibodies have been found in adults compared with children78

Higher numbers of cross-reactive T cells found in eldery80

The role of cross-reactive T cells remains unclear88–90

Unlikely to explain lower severity extending into early adulthood

Differences in the microbiota might influence susceptibility to SARS-CoV-2

Microbial interactions and competition might limit colonisation and growth of SARS-CoV-2154 155

ACE2 highly expressed in the nasopharynx and gastrointestinal tract152 153

Observed differences in the gastrointestinal microbiota between patients infected with SARS-CoV-2 and healthy controls160–162

Administration of probiotics leads to quicker improvement of COVID-19-related symptoms227

Higher melatonin levels

Children have higher levels of melatonin190 191

Bats, which suffer from minimal or no symptoms of CoV infection, have higher levels of melatonin compared with humans189

Melatonin inhibits calmodulin which increases ACE2 expression and retention on cell surface180 181

In silico studies suggest that melatonin inhibits SARS-CoV-2’s main protease185

More recent vaccination with live vaccines that have off-target effects

Trials show BCG-induced protection against viral infections194 195

Possible correlation between different BCG countries’ vaccination policies and severity of COVID-19200–202

More recent BCG, MMR and OPV vaccination in younger age groups might protect against severe COVID-19199 208 209

Off-target immunomodulatory effects are unlikely to be long lasting205 206

Many other explanations for differences between countries’ rate and severity of COVID-19203 205

Severity of COVID-19 associated with initial viral load

Children are predominantly infected by transmission from adults6 208 209

Children have less workplace, shopping, travel and nosocomial exposure to SARS-CoV-2

For SARS-CoV and MERS-CoV, subsequent generations of virus with reduced pathogenicity reported217 218

No evidence for reduced virulence of SARS-CoV-2 in second-generation infections219 220