Table 1

Proposed hypotheses for the age-related difference in severity of COVID-19

Key factors
Proposed mechanism In support of hypothesis Against hypothesis
(1) Endothelium and clotting function
Endothelial damage and hypercoagulable state
  • 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

(2) ACE2 receptors and TMPRSS2
Viral entry
  • 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

(3) Pre-existing immunity
Cumulative exposure to commonly circulating HCoVs (229E, HKU1, NL63, OC43)
  • 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

(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
  • 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

(6) Vitamin D
Anti-inflammatory and anti-oxidative properties
  • 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

Key factors
Proposed mechanism In support of hypothesis Against hypothesis
(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
  • 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

(3) Cross-reactive coronavirus antibodies and T cells
Exposure to commonly circulating HCoV (229E, HKU1, NL63, OC43)
  • 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

(4) Microbiota (nasopharyngeal, oropharyngeal, lung and/or gastrointestinal)
Colonising microbial flora
  • 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

(5) Melatonin
Anti-inflammatory and anti-oxidative properties
  • 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

(6) Off-target effects of live vaccines
Trained immunity from BCG, MCV, OPV
  • 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

(7) Exposure
Intensity of viral exposure
  • 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

  • ACE2, angiotensin converting enzyme 2; ARDS, acute respiratory distress syndrome; CMV, cytomegalovirus; HCoV, human coronavirus; IFN, interferon; IL, interleukin; MCV, measles-containing vaccine; MERS-CoV, Middle East respiratory syndrome coronavirus; MMR, measles-mumps-rubella; NK, natural killer; NLRP3, NOD-containing, LRR-containing and pyrin domain-containing protein 3; OPV, oral polio vaccine; RSV, respiratory syncytial virus; TMPRSS2, transmembrane serine protease 2; TNF, tumour necrosis factor.