Why Does the Severity of COVID-19 Differ With Age?

Abstract

Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterologous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflammatory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2. There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load.

Diagnosis and management of post-COVID (Long COVID) in children: a moving target

“…The Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) has posed several challenges to the global population, in terms of morbidity and mortality, economic impact and social implications. The clinical impact on children has been overall milder compared with adults, in terms of disease severity and deaths [1], although also in the paediatric population hospitalizations, deaths and severe acute complications like the Multisystem Inflammatory Syndrome (MIS-C) have been recorded globally [2]. Later during the pandemic, patients and early follow-up data highlighted that a group of adults were still reporting a number of persisting symptoms (e.g.…”

Younger Children Develop Higher Effector Antibody Responses to SARS-CoV-2 Infection

“…recently proposed that the higher levels of SARS-CoV-2 antibodies observed in children as compared with adults result from the back-boosting of a higher preexisting immunity to beta HCoVs [ 19 , 20 ]. This model is not supported by our results showing that antibody levels to beta HCoVs follow an inverse relationship with age as compared with antibody levels to SARS-CoV-2, with higher levels in older as compared with younger children, most likely because of repeated exposures [ 14 ]. Our detailed analysis of the antibody response to individual domains of the S protein provides important insight into the role of cross-reactive immunity to HCoVs in the antibody response to SARS-CoV-2 infection in children.…”

“…The mechanism that could underlie the inverse association between child age and levels of SARS-CoV-2 antibodies is unclear. The robust innate immune response detected early during the course of SARS-CoV-2 infection in children is likely to play a role [ 5 , 13 , 14 , 16 ]. Trained immunity induced by common infections or vaccinations may contribute too [ 14 ].…”

“…The robust innate immune response detected early during the course of SARS-CoV-2 infection in children is likely to play a role [ 5 , 13 , 14 , 16 ]. Trained immunity induced by common infections or vaccinations may contribute too [ 14 ]. Our observation that avidity of RBD-specific IgG inversely correlated with age of children suggests that younger children have a unique capacity to develop effective germinal center reactions in response to SARS-CoV-2 infection.…”

“…Innate immunity involving type I interferons is essential for the control of SARS-CoV-2 replication during the early phase of the infection, whereas excessive innate immune responses play a pathogenic role later in the course of COVID-19 [ 12 ]. Children with mild COVID-19 develop robust innate immune responses that resolve faster than in adults, suggesting efficient control of inflammatory responses [ 5 , 13 , 14 ]. On the other hand, adaptive immune responses are essential to clear SARS-CoV-2 infection and provide immunity to re-infections with homologous SARS-CoV-2 or variants thereof [ 15 ].…”