Why Children Are Less Affected by COVID-19 Than Adults: Potential Immunological Factors and the Renin-Angiotensin System Associated Mechanisms

Abstract

The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.

Molecular Determinants of the Early Life Immune Response to COVID-19 Infection and Immunization

“…Although SARS-CoV-2 virus shedding varies among individuals [ 8 ], infected children can shed SARS-CoV-2 virus with nasopharyngeal viral loads comparable to or higher than those in adults [ 9 , 10 ]. Emerging literature on pediatric COVID-19 is focused on finding an explanation for the lower severity of infection observed in this population [ 11 , 12 , 13 ]. While a definitive answer to this query is unknown, age-related differences in immune system function may explain the higher susceptibility to serious events in adults.…”

“…The resulting impairment in early life to promote T-helper 1 immunity to novel pathogens can prime the immune system of children to the preferential induction of a tolerogenic or sometimes detrimental T-helper 2 response [ 29 , 32 , 33 ]. While these intrinsic features of the developing immune system may have proven disadvantageous in the context of other respiratory viruses such as RSV [ 34 , 35 , 36 , 37 , 38 ], it has been postulated that in the context of SARS-CoV-2 this may contribute to reduced disease burden in this age group [ 11 ]. In addition, investigation into the age-specific differences in pathology and immune response to infection could contribute to improved future vaccine formulations tailored for children.…”