Hypothesis
Key factors |
Proposed mechanism
|
In support of hypothesis
|
Against hypothesis
|
(A) FACTORS INCREASING RISK IN ADULTS
|
(1) Endothelium and clotting function
|
Endothelial damage and hypercoagulable state |
|
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
| |
(2) ACE2 receptors and TMPRSS2
|
Viral entry |
|
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
|
(3) Pre-existing immunity
|
Cumulative exposure to commonly circulating HCoVs (229E, HKU1, NL63, OC43) |
|
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
| |
(4) Immunosenescence and inflammaging
|
Age-related changes in the immune system including chronic CMV infection |
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
| |
(5) Comorbidities
|
Obesity, diabetes, hypertension, chronic lung, heart and kidney disease, and smoking |
|
|
|
(6) Vitamin D
|
Anti-inflammatory and anti-oxidative properties |
|
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
| |
Hypothesis
Key factors |
Proposed mechanism
|
In support of hypothesis
|
Against hypothesis
|
(B) FACTORS PROTECTING CHILDREN
|
(1) Immune system
|
Age-related differences in immune response |
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
|
(2) Recurrent and concurrent infections
|
Viral and mycoplasma infections |
|
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
| |
(3) Cross-reactive coronavirus antibodies and T cells
|
Exposure to commonly circulating HCoV (229E, HKU1, NL63, OC43) |
| |
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
|
(4) Microbiota (nasopharyngeal, oropharyngeal, lung and/or gastrointestinal)
|
Colonising microbial flora |
|
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
| |
(5) Melatonin
|
Anti-inflammatory and anti-oxidative properties |
|
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
| |
(6) Off-target effects of live vaccines
|
Trained immunity from BCG, MCV, OPV |
|
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
|
|
(7) Exposure
|
Intensity of viral exposure |
|
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
|
|