key: cord-1010389-xvfawxs5 authors: Falahi, Shahab; Abdoli, Amir; Kenarkoohi, Azra title: Claims and reasons about mild COVID- 19 infection in children date: 2021-03-17 journal: New Microbes New Infect DOI: 10.1016/j.nmni.2021.100864 sha: b13861a728701c3f5b21a5768c2357ae27688f1a doc_id: 1010389 cord_uid: xvfawxs5 The elderly is the main risk group in the COVID- 19 pandemic, and aging is recognized as a major risk factor for the severity of infection and mortality of COVID- 19. The severity of the infection in children is milder than in adults. Although the pathophysiology of COVID- 19 infection is not fully understood, several possible factors and mechanisms have been suggested for lower severity of infection in children. The COVID-19 pandemic is still continuing and millions cases of infected people reported (1) . SARS-CoV-2, with its high transmissibility, has been putting a lot of stress on the world since late 2019, and the effects of this infection on the human population are still being studied (2, 3) . SARS-CoV-2 reinfection remains to be fully clarified. Children with broad spectrum of ages can be infected by coronavirus disease 2019 and most infected children do not show symptoms or their disease is less severe than adults as well as recover 1-2 weeks post symptoms onset (4, 5) . According to CDC data, in the United States children by age <18 years represent 1.7% to 12% of all COVID-19 cases (5, 6) . Although serious illness in children with COVID-19 are reported, but their hospitalization are also much lower than its rates for adults (5) . Both children and adults are susceptible to COVID-19, while outcomes as well as clinical presentations were more favorable for children (4, 7) . According to contact tracing data, children mostly are not the index patients and they infected with SARS-Cov-2 virus from adults. Additionally secondary infections from children source were also uncommon (4) . Although serious illness in children with COVID-19 were reported but it is uncommon to hospitalize or experience death (5, 8) however, a small number of deaths were also identified(9). J o u r n a l P r e -p r o o f Like adults, children suffering from underlying disease, such as diabetes, obesity, congenital heart disease, genetic conditions or conditions affecting the nervous system or metabolism have higher risk for serious complication of COVID-19 (10, 11) . It is now accepted that COVID-19 disease is less severe in children and infants than adults. Several hypothesis and possible mechanism that may cause a mild infection in children were proposed. Angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 receptor. It seems that ACE2 expression in the respiratory tract of children is less than that of adults (12) . In addition, in adults, due to underlying problems and the use of some drugs such as ACE inhibitors, ACE2 expression increases, which in turn increases the virus entry into cells (13) , but some researchers believe in the ACE2 protective effects in lung disease (14) . ACE2 has two forms: membrane-bound form and soluble form. Some also believe that soluble ACE2 is more common in children than adults, and that this form of ACE2 acts like neutralizing antibody and neutralizes SARS-CoV-2, in other words, the soluble ACE2 in children has a protective role (15, 16) . A group of researchers suggested that bradykinin storm in patients with COVID -19 is responsible for many of the clinical symptoms of the disease, and changes in the reninangiotensin system (RAS) in COVID -19 patients lead to increased bradykinin levels. Bradykinin is one of the important components in regulating blood pressure and reduces blood pressure with its vasodilatory role. In addition, bradykinin increases vascular permeability and edema in lung tissue. Increased bradykinin levels in the body cause pain and induce neutrophils to inflammatory tissue. Increased bradykinin has been reported to cause symptoms such as dry cough, an initial decrease in o2 saturation, and increased vascular permeability (17) . Bradykinin is further degraded and inactivated by ACE. Children have more ACE in the serum than adults, so it can be hypothesized that children break down bradykinin more than adults, so they do not show the side effects of elevated bradykinin levels. J o u r n a l P r e -p r o o f The endothelium and the coagulation system are also different in children compared with adults, which makes children less susceptible to thrombotic complications (18) into the endothelium and a decrease in ACE2 on endothelial cells, followed by an increase in angiotensin 2, it increases inflammation and coagulation. Children generally have healthy vascular and less endothelial damage. In adults, the endothelium is more vulnerable and the presence of cardiovascular disease exacerbates vascular damage (19) . The characteristics of the respiratory tissues of children and adults are also different: In adults, reduction of ciliary movement of cells in the respiratory tract can be an important factor in the rapid access of the virus to the lower respiratory tract, a feature that is not present in children's respiratory system .In addition, children's lungs may have a greater capacity for repair after infection (20) . One of the important risk factors for the severity of COVID -19 disease is underlying diseases. And as we know, the prevalence of underlying diseases is higher in adults than in children (21, 22) . Immune system differences are probably one of the main reasons for the difference in disease severity between children and adults (19) . Some infections and vaccinations can provide extensive protection against other infectious agents through innate immune mechanisms. This J o u r n a l P r e -p r o o f process is called trained immunity. Trained immunity is the memory of an innate immune system that acts non-specifically without producing antibodies. Trained immunity although reversible and short-lived (23), the frequency of childhood vaccinations causes sufficient trained immunity in this period. Vaccines, such as BCM bacillus (BCG), can increase the basal level of innate immunity and stimulate resistance to other pathogens like COVID-19(known as trained innate immunity). Then child's immune system is ready to respond quickly to pathogens (19) . Some live vaccines have non-specific immunomodulatory effects rather than protection against their target pathogens as well as it has been postulated that this contributes to age-related difference in COVID-19 severity (24, 25) supported by fact that children have also generally been vaccinated with BCG and other live attenuated vaccines more recently ant frequently than adults(24, 26). On the other hand, the presence of natural antibodies is more in children, which are actually part of the innate immune system and cause a faster response to infectious agents. Natural antibodies contain the infection until the acquired immune system is activated and antigen-specific antibodies are produced (27) . Another point is cross-immunity, it is also possible that common cold coronaviruses in children have caused cross-protection against SARS-CoV-2 (15) . Like other organs and systems, the immune system can be affected by aging. According to several studies, aging causes changes in the body's immune factors and may lead to a decrease in the strength of immune responses, a phenomenon called immunosenescence. In addition to, inflammation is beneficial if it is short-lived and controlled, but it is harmful if it is severe and uncontrollable. One possible mechanism of COVID-19 pathogenesis is the overproduction of inflammatory cytokines called cytokine storms. In children, the production of inflammatory cytokines is lower than in adults, and the amount of pro-inflammatory cytokines increases with age. Cytokine storms are more likely to occur in adults than in children. In general, Inflammation increases with age, a phenomenon also known as "inflame-aging" also, the production of interleukin-6 increases with age. Interleukin 6 is the major cytokine in the formation of cytokine storms. In fact, increased production of inflammatory cytokines, especially interleukin 6, in adults compared to children leads to a higher chance of developing a cytokine storm in adults than in children (28) . In addition, the hyperinflammation underlying pediatric inflammatory Children naso/oropharynx often colonized with communities of viruses and bacteria more than adults, where their interactions and competition with invading organism might limit the growth and spread of infecting organism such as SARS-CoV-2 (45, 46). As many other infections, viral load affect the severity of outcome in COVID-19, that proposed lower viral exposure dose may be another factor responsible for to less severe outcome (47) (48) (49) . probably lower pathogenicity. The thymus is a lymphoid organ that degenerate during aging and its activity changing during childhood to adulthood and differences in its activity may affect the severity of COVID-19 disease in children and adults (51) . Thymus atrophy is one of the immunosenescence etiology in elderly that leads to Inflammaging (52) . As the thymus degenerates in the elderly, production of naïve T-cell and T-cell receptor (TCR) repertoire diversity decrease, which can lead to weakened immune responses, especially to new infectious agents in the elderly (51, 52) . Sex hormones have been proposed as one of the possible factors affecting the differences in severity of COVID-19 infection between male and female. Female sex hormones appear to have J o u r n a l P r e -p r o o f a protective effect against COVID-19 infection by acting on the immune system and their antiinflammatory role (16, 53) . Although it should be noted that, generally the level of sex hormones in children is lower than adults, further research efforts are required to investigate the putative effect and mechanism of sex hormones on disease severity. SARS-CoV-2 entry depends on ACE2 via employing TMPRSS2 serine protease activity for S protein priming (28, 54) . Androgen hormones increase the expression of TMPRSS2, given that level of sex hormones in children significantly lower compared to adults, they may have lower expression of TMPRSS2 and as a result SARS-CoV-2 entry and replication in children might be limited (54) . As well as, the relationship between sex hormones and renin-angiotensin system is complex and controversial and sex hormones appear to affect ACE2 expression (55, 56) , which differences in levels of these hormones in children and adults may affect the severity of disease between them. Although there are several points of view responsible for less sever COVID-19 infection in children, especially age-related difference in immune responses and different endothelial system function or physiology, the exact mechanisms/determinants of the COVID-19 outcome, between children and adults are still unclear. Many more investigation based on well randomized case control studies have to be performing for proving the reality and reason of less sever outcome of COVID-19 infection in children by great detail. The severity of the COVID-19 infection in children is milder than in adults. It seems that ACE2 expression in the respiratory tract of children is less than that of adults. Soluble ACE2 in children has a protective role. Children generally have healthy vascular and less endothelial damage. One of the important risk factors for the severity of COVID -19 disease is underlying diseases, the prevalence of underlying diseases is higher in adults than in children. The frequency of childhood vaccinations causes sufficient trained immunity in this period. Presence of natural antibodies is more in children than adults, which cause a faster response to infectious agents. 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